Crbn ligands and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of CRBN, and the treatment of CRBN-mediated disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/961,362, filed Jul. 10, 2020, which is a national stage filing underU.S.C. § 371 of PCT International Application PCT/US2019/013491, filedJan. 14, 2019, which claims the benefit of U.S. Provisional ApplicationNo. 62/616,713, filed Jan. 12, 2018, the entirety of each of which ishereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forbinding and modulating the activity of cereblon (CRBN). The inventionalso provides pharmaceutically acceptable compositions comprisingcompounds of the present invention and methods of using saidcompositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The Ubiquitin-Proteasome Pathway (UPP) is a critical pathway thatregulates key regulator proteins and degrades misfolded or abnormalproteins. UPP is central to multiple cellular processes, and ifdefective or imbalanced, it leads to pathogenesis of a variety ofdiseases. The covalent attachment of ubiquitin to specific proteinsubstrates is achieved through the action of E3 ubiquitin ligases. Theseligases comprise over 500 different proteins and are categorized intomultiple classes defined by the structural element of their E3functional activity.

UPP plays a key role in the degradation of short-lived and regulatoryproteins important in a variety of basic cellular processes, includingregulation of the cell cycle, modulation of cell surface receptors andion channels, and antigen presentation. The pathway has been implicatedin several forms of malignancy, in the pathogenesis of several geneticdiseases (including cystic fibrosis, Angelman's syndrome, and Liddlesyndrome), in immune surveillance/viral pathogenesis, and in thepathology of muscle wasting. Many diseases are associated with anabnormal UPP and negatively affect cell cycle and division, the cellularresponse to stress and to extracellular modulators, morphogenesis ofneuronal networks, modulation of cell surface receptors, ion channels,the secretory pathway, DNA repair and biogenesis of organelles.

Aberrations in the process have recently been implicated in thepathogenesis of several diseases, both inherited and acquired. Thesediseases fall into two major groups: (a) those that result from loss offunction with the resultant stabilization of certain proteins, and (b)those that result from gain of function, i.e. abnormal or accelerateddegradation of the protein target.

Cereblon (CRBN) interacts with damaged DNA binding protein 1 and formsan E3 ubiquitin ligase complex with Cullin 4 where it functions as asubstrate receptor in which the proteins recognized by CRBN might beubiquitinated and degraded by proteasomes.

A new role for CRBN has been identified; i.e., the binding ofimmunomodulatory drugs (IMiDs), e.g. thalidomide, to CRBN has now beenassociated with teratogenicity and also the cytotoxicity of IMiDs,including lenalidomide, which are widely used to treat multiple myelomapatients. CRBN is likely a key player in the binding, ubiquitination anddegradation of factors involved in maintaining function of myelomacells. These new findings regarding the role of CRBN in IMiD actionstimulated intense investigation of CRBN's downstream factors involvedin maintaining regular function of a cell (Chang and Stewart Int JBiochem Mol Biol. 2011; 2(3): 287-294).

Accordingly, there remains a need to find CRBN ligands useful astherapeutic agents.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective as CRBNligands. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

It has also been found that other compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective as CRBNligands. Such compounds have the general formula I′:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions associated with CRBN. Such diseases, disorders,or conditions include those described herein.

Compounds provided by this invention are also useful for the study ofCRBN and associated proteins in biological and pathological phenomena;the study of CRBN occurring in bodily tissues; and the comparativeevaluation of new CRBN ligands or other regulators of CRBN in vitro orin vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulas CRBN ligands.

As defined herein, the terms “binder,” “modulator,” and “ligand” areused interchangeably and describe a compound that binds to, modulates,or is a ligand for CRBN.

Without being bound by any particular theory, it is believed that thecompounds of the present invention exert their effects by binding toCRBN, recruiting a protein substrate which results in ubiquitination bythe E3 complex and subsequent degradation of the protein by theproteosome. This results in phenotypes such as, for example, decreasedviability of cancer cells.

In one aspect, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is selected from

-   each of X¹ and X⁶ is independently a bivalent moiety selected from a    covalent bond, —O—, —CH₂—, —C(R¹)H—, —C(R¹)₂—, —C(O)—, —C(NR¹)—,    —C(S)—, or

-   X² is a trivalent moiety selected from

-   each of X³ and X⁴ is independently a bivalent moiety selected from a    covalent bond, —O—, —S—, —S(O)—, —S(O)₂—, or —N(R)—;-   X⁵ is a bivalent moiety selected from a covalent bond, —O—, —CH₂—,    —C(R¹)H—, —C(R¹)₂—, —C(NR¹)—, —C(S)—, or

-   each R is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; or    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, or sulfur;-   each R¹ is independently hydrogen, deuterium, halogen, —CN, —OR,    —SR, —S(O)R, —S(O)₂R, —N(R)₂, or an optionally substituted C₁₋₄    aliphatic; or    -   two R¹ groups on the same carbon are optionally taken together        with their intervening atoms to form a 3-6 membered spiro fused        ring; or    -   two R¹ groups on adjacent carbon atoms are optionally taken        together with their intervening atoms to form a 3-6 membered        saturated, partially unsaturated, or aryl fused ring having 0-2        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;-   each R² is independently hydrogen, halogen, —CN, —NO₂, —OR, —SR,    —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, an optionally substituted 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, or an optionally substituted 5-6 membered heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2 methylene    units of L are independently and optionally replaced by —O—, —NR—,    —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NR³S(O)₂—,    —S(O)₂NR³—, —NR³C(O)—, —C(O)NR³—, —OC(O)NR³—, —NR³C(O)O—,

-    provided that L is other than a covalent bond, —CH₂—, —C(O)O—,    —C(O)OCH₂—, —CH₂C(O)—, —C(O)CH₂—, —N(R)C(O)—, —C(O)N(R)—, or    —CH₂CH₂— when Ring A is

-    and X¹ is —C(O)— or Ring A is

-    and X² is or

-   each R³ is independently hydrogen or C₁₋₄ aliphatic;-   Ring B is selected from a 4 to 7-membered saturated or partially    unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic    carbocyclic aromatic ring, a 5 to 7-membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6-membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, wherein Ring B is optionally further substituted with 1-2    oxo groups;-   m is 0, 1, 2, 3, or 4; and-   n is 0, 1, 2, 3, or 4.

In another aspect, the present invention provides a compound of FormulaI′:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is selected from

-   each of X¹, X⁵, and X⁶ is independently a bivalent moiety selected    from a covalent bond, —O—, —S—, —C(R¹)CF₃—, —C(R¹)₂—, —C(O)—,    —N(R¹)—, —C(NR¹)—, —C(S)—, —Si(R¹)₂—, —P(O)(R¹)—, —P(O)(OR¹)—,    —P(O)N(R¹)₂—, or

-   X² is a trivalent moiety selected from

-   each of X³ and X⁴ is independently a bivalent moiety selected from a    covalent bond, —O—, —S—, —C(R¹)F—, —CF₂—, —C(R¹)₂—, —S(O)—, —S(O)₂—,    —Si(R¹)₂—, —P(O)(R¹)—, or —N(R)—;-   each R is independently hydrogen, deuterium, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 7-13 membered saturated, partially    unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring    having 1-3 heteroatoms, independently selected from boron, nitrogen,    oxygen, silicon, or sulfur, and a 8-10 membered bicyclic heteroaryl    ring having 1-4 heteroatoms, independently selected from boron,    nitrogen, oxygen, silicon, or sulfur; or    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-8 membered saturated,        partially unsaturated, or heteroaryl monocyclic ring having 0-1        heteroatom, in addition to the nitrogen, independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 0-2 heteroatoms, in        addition to the nitrogen, independently selected from boron,        nitrogen, oxygen, silicon, or sulfur;-   each R¹ is independently hydrogen, deuterium, halogen, —CN, —OR,    —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,    —Si(OH)R₂, —Si(OH)₂R, —SiR₃, or an optionally substituted C₁₋₄    aliphatic; or    -   R¹ and X¹ or X⁴ are taken together with their intervening atoms        to form a 5-7 membered saturated, partially unsaturated,        carbocyclic ring or heterocyclic ring having 1-3 heteroatoms,        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;    -   two R¹ groups on the same carbon are optionally taken together        with their intervening atoms to form a 3-6 membered spiro fused        ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;    -   two R¹ groups on adjacent carbon atoms are optionally taken        together with their intervening atoms to form a 3-7 membered        saturated, partially unsaturated, carbocyclic ring or        heterocyclic ring having 1-3 heteroatoms independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 1-3 heteroatoms,        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;-   each R² is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OR, —SR, —NR₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂,    —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —N(R)S(O)₂NR₂,    —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, optionally substituted C₁₋₆    aliphatic, optionally substituted phenyl, optionally substituted 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, optionally substituted 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from boron,    nitrogen, oxygen, silicon, or sulfur, optionally substituted 7-13    membered saturated, partially unsaturated, bridged heterocyclic    ring, or a spiro heterocyclic ring having 1-3 heteroatoms,    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2 methylene    units of L are independently and optionally replaced by —O—, —NR³—,    —S—, —OC(O)—, —C(O)O—, —C(O)—, —Si(R¹)₂—, —P(O)(R¹)—, —P(O)(OR)—,    —P(O)(NR₂)—, —S(O)—, —S(O)₂—, —NR³(O)₂—, —S(O)₂NR³—, —NR³C(O)—,    —C(O)NR³—, —OC(O)NR³—, —NR³C(O)O—,

-    provided that L is other than a covalent bond or a bivalent,    saturated or unsaturated, straight or branched C₁₋₆ hydrocarbon    chain, wherein 1-2 methylene units of L are independently and    optionally replaced by —O—, —NR—, —OC(O)—, —C(O)O—, —C(O)—,    —NR³S(O)₂—, —S(O)₂NR³—, —N(R)C(O)—, —C(O)N(R)—, or —NR³C(O)O— when    Ring A is

-    and X¹ is —C(O)—, Ring A is

-    and X² is

-    Ring A is

-    and X² is

-    Ring A is

-    Ring A is

-    and X¹ is —C(O)— or —CH₂— or Ring A is

-    and X² is

-   each R³ is independently hydrogen, deuterium, or optionally    substituted C₁₋₄ aliphatic; Ring B is selected from a 3 to    7-membered saturated or partially unsaturated carbocyclic ring,    phenyl, 8-10 membered bicyclic carbocyclic aromatic ring, 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, 7-13 membered saturated, partially unsaturated,    bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, or a 8-10 membered bicyclic heteroaryl ring    having 1-4 heteroatoms, independently selected from boron, nitrogen,    oxygen, silicon, or sulfur; wherein Ring B is optionally further    substituted with 1-2 oxo groups;-   m is 0, 1, 2, 3, or 4; and-   n is 0, 1, 2, 3, or 4.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms“heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(◯); —(CH₂)₀₋₄OR^(◯); —O(CH₂)₀₋₄R^(◯), —O—(CH₂)₀₋₄C(O)OR^(◯);—(CH₂)₀₋₄CH(OR^(◯))₂; —(CH₂)₀₋₄SR^(◯); —(CH₂)₀₋₄Ph, which may besubstituted with R^(◯); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(◯); —CH═CHPh, which may be substituted with R^(◯);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(◯); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(◯))₂; —(CH₂)₀₋₄N(R^(◯))C(O)R^(◯);—N(R^(◯))C(S)R^(◯); —(CH₂)₀₋₄N(R^(◯))C(O)NR^(◯) ₂; —N(R^(◯))C(S)NR^(◯)₂; —(CH₂)₀₋₄N(R^(◯))C(O)OR^(◯); —N(R^(◯))N(R^(◯))C(O)R^(◯);—N(R^(◯))N(R^(◯))C(O)NR^(◯) ₂; —N(R^(◯))N(R^(◯))C(O)OR^(◯);—(CH₂)₀₋₄C(O)R^(◯); —C(S)R^(◯); —(CH₂)₀₋₄C(O)OR^(◯);—(CH₂)₀₋₄C(O)SR^(◯); —(CH₂)₀₋₄C(O)OSiR^(◯)3; —(CH₂)₀₋₄OC(O)R^(◯);—OC(O)(CH₂)₀₋₄SR^(◯); —SC(S)SR^(◯); —(CH₂)₀₋₄SC(O)R^(◯);—(CH₂)₀₋₄C(O)NR^(◯)2; —C(S)NR^(◯) ₂; —C(S)SR^(◯); —(CH₂)₀₋₄OC(O)NR^(◯)₂; —C(O)N(OR^(◯))R^(◯); —C(O)C(O)R^(◯); —C(O)CH₂C(O)R^(◯);—C(NOR^(◯))R^(◯); —(CH₂)₀₋₄SSR^(◯); —(CH₂)₀₋₄S(O)₂R^(◯);—(CH₂)₀₋₄S(O)₂OR^(◯); —(CH₂)₀₋₄OS(O)₂R^(◯); —S(O)₂NR^(◯) ₂;—(CH₂)₀₋₄S(O)R^(◯); —N(R^(◯))S(O)₂NR^(◯) ₂; —N(R^(◯))S(O)₂R^(◯);—N(OR^(◯))R^(◯); —C(NH)NR^(◯) ₂; —P(O)₂R^(◯); —P(O)R^(◯) ₂; —OP(O)R^(◯)₂; —OP(O)(OR^(◯))₂; —SiR^(◯) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(◯))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(◯))₂, wherein each R^(◯) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(◯), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(◯) (or the ring formed by takingtwo independent occurrences of R^(◯) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂₀R^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●)3, —OSiR^(●)3, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(◯) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a provided compound may be substituted with one or moredeuterium atoms.

As used herein, the term “provided compound” refers to any genus,subgenus, and/or species set forth herein.

As used herein, the term “binder” or “ligand” is defined as a compoundthat binds to CRBN with measurable affinity. In certain embodiments, acompound has a binding constant of less than about 50 μM, less thanabout 1 μM, less than about 500 nM, less than about 100 nM, less thanabout 10 nM, or less than about 1 nM.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably modulate,” as usedherein, means a measurable change in a CRBN activity between a samplecomprising a compound of the present invention, or composition thereof,and CRBN, and an equivalent sample comprising CRBN, in the absence ofsaid compound, or composition thereof.

3. Description of Exemplary Embodiments

As described above, in one aspect, the present invention provides acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is selected from

-   each of X¹ and X⁶ is independently a bivalent moiety selected from a    covalent bond, —O—, —CH₂—, —C(R¹)H—, —C(R¹)₂—, —C(O)—, —C(NR¹)—,    —C(S)—, or

-   X² is a trivalent moiety selected from

-   each of X³ and X⁴ is independently a bivalent moiety selected from a    covalent bond, —O—, —S—, —S(O)—, —S(O)₂—, or —N(R)—;-   X⁵ is a bivalent moiety selected from a covalent bond, —O—, —CH₂—,    —C(R¹)H—, —C(R¹)₂—, —C(NR¹)—, —C(S)—, or

-   each R is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, and a 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; or    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, or sulfur;-   each R¹ is independently hydrogen, deuterium, halogen, —CN, —OR,    —SR, —S(O)R, —S(O)₂R, —N(R)₂, or an optionally substituted C₁₋₄    aliphatic; or    -   two R¹ groups on the same carbon are optionally taken together        with their intervening atoms to form a 3-6 membered spiro fused        ring; or    -   two R¹ groups on adjacent carbon atoms are optionally taken        together with their intervening atoms to form a 3-6 membered        saturated, partially unsaturated, or aryl fused ring having 0-2        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;-   each R² is independently hydrogen, halogen, —CN, —NO₂, —OR, —SR,    —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,    —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R,    —N(R)C(O)NR₂, —N(R)S(O)₂R, optionally substituted C₁₋₆ aliphatic,    optionally substituted phenyl, an optionally substituted 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from nitrogen, oxygen, or    sulfur, or an optionally substituted 5-6 membered heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2 methylene    units of L are independently and optionally replaced by —O—, —NR—,    —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NR³S(O)₂—,    —S(O)₂NR³—, —NR³C(O)—, —C(O)NR³—, —OC(O)NR³—, —NR³C(O)O—,

-    provided that L is other than a covalent bond, —CH₂—, —C(O)O—,    —C(O)OCH₂—, —CH₂C(O)—, —C(O)CH₂—, —N(R)C(O)—, —C(O)N(R)—, or    —CH₂CH₂— when Ring A is

-    and X¹ is

-    and X² is

-   each R³ is independently hydrogen or C₁₋₄ aliphatic;-   Ring B is selected from a 4 to 7-membered saturated or partially    unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic    carbocyclic aromatic ring, a 5 to 7-membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, a 5-6-membered heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, wherein Ring B is optionally further substituted with 1-2    oxo groups;-   m is 0, 1, 2, 3, or 4; and-   n is 0, 1, 2, 3, or 4.

In some embodiments, the present invention provides a compound ofFormula I or a pharmaceutically acceptable salt thereof, in which L isother than a covalent bond, —CH₂—, —C(O)O—, —C(O)OCH₂—, —CH₂C(O)—,—C(O)CH₂—, —N(R)C(O)—, —C(O)N(R)—, or —CH₂CH₂— when Ring A is

and X¹ is —C(O)— or Ring A is

and X² is

and wherein the compound is other than a compound listed in Table 2.

In another aspect, the present invention provides a compound of FormulaI′:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is selected from

-   each of X¹, X⁵, and X⁶ is independently a bivalent moiety selected    from a covalent bond, —O—, —S—, —C(R¹)CF₃—, —C(R¹)₂—, —C(O)—,    —N(R¹)—, —C(NR¹)—, —C(S)—, —Si(R¹)₂—, —P(O)(R¹)—, —P(O)(OR¹)—,    —P(O)N(R¹)₂—, or

-   X² is a trivalent moiety selected from

-   each of X³ and X⁴ is independently a bivalent moiety selected from a    covalent bond, —O—, —S—, —C(R¹)F—, —CF₂—, —C(R¹)₂—, —S(O)—, —S(O)₂—,    —Si(R¹)₂—, —P(O)(R¹)—, or —N(R)—;-   each R is independently hydrogen, deuterium, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 7-13 membered saturated, partially    unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring    having 1-3 heteroatoms, independently selected from boron, nitrogen,    oxygen, silicon, or sulfur, and a 8-10 membered bicyclic heteroaryl    ring having 1-4 heteroatoms, independently selected from boron,    nitrogen, oxygen, silicon, or sulfur; or    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-8 membered saturated,        partially unsaturated, or heteroaryl monocyclic ring having 0-1        heteroatom, in addition to the nitrogen, independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 0-2 heteroatoms, in        addition to the nitrogen, independently selected from boron,        nitrogen, oxygen, silicon, or sulfur;-   each R¹ is independently hydrogen, deuterium, halogen, —CN, —OR,    —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,    —Si(OH)R₂, —Si(OH)₂R, —SiR₃, or an optionally substituted C₁₋₄    aliphatic; or    -   R¹ and X¹ or X⁴ are taken together with their intervening atoms        to form a 5-7 membered saturated, partially unsaturated,        carbocyclic ring or heterocyclic ring having 1-3 heteroatoms,        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;    -   two R¹ groups on the same carbon are optionally taken together        with their intervening atoms to form a 3-6 membered spiro fused        ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;    -   two R¹ groups on adjacent carbon atoms are optionally taken        together with their intervening atoms to form a 3-7 membered        saturated, partially unsaturated, carbocyclic ring or        heterocyclic ring having 1-3 heteroatoms independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 1-3 heteroatoms,        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;-   each R² is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OR, —SR, —NR₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂,    —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —N(R)S(O)₂NR₂,    —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, optionally substituted C₁₋₆    aliphatic, optionally substituted phenyl, optionally substituted 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, optionally substituted 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from boron,    nitrogen, oxygen, silicon, or sulfur, optionally substituted 7-13    membered saturated, partially unsaturated, bridged heterocyclic    ring, or a spiro heterocyclic ring having 1-3 heteroatoms,    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2 methylene    units of L are independently and optionally replaced by —O—, —NR—,    —S—, —OC(O)—, —C(O)O—, —C(O)—, —Si(R¹)₂—, —P(O)(R¹)—, —P(O)(OR)—,    —P(O)(NR₂)—, —S(O)—, —S(O)₂—, —NR³S(O)₂—, —S(O)₂NR³—, —NR³C(O)—,    —C(O)NR³—, —OC(O)NR³—, —NR³C(O)O—,

-    provided that L is other than a covalent bond or a bivalent,    saturated or unsaturated, straight or branched C₁₋₆ hydrocarbon    chain, wherein 1-2 methylene units of L are independently and    optionally replaced by —O—, —NR³—, —OC(O)—, —C(O)O—, —C(O)—,    —NR³S(O)₂—, —S(O)₂NR³—, —N(R)C(O)—, —C(O)N(R)—, or —NR³C(O)O— when    Ring A is

-    and X¹ is —C(O)—, Ring A is

-    and X² is

-    Ring A is

-    and X² is

-    Ring A is

-    Ring A is

-    and X¹ is —C(O)— or —CH₂—, or Ring A is

-    and X² is

-   each R³ is independently hydrogen, deuterium, or optionally    substituted C₁₋₄ aliphatic;-   Ring B is selected from a 3 to 7-membered saturated or partially    unsaturated carbocyclic ring, phenyl, 8-10 membered bicyclic    carbocyclic aromatic ring, 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, 7-13    membered saturated, partially unsaturated, bridged heterocyclic    ring, or a spiro heterocyclic ring having 1-3 heteroatoms,    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur; wherein Ring B is optionally further substituted    with 1-2 oxo groups;-   m is 0, 1, 2, 3, or 4; and-   n is 0, 1, 2, 3, or 4.

In some embodiments, the present invention provides a compound ofFormula I′, or a pharmaceutically acceptable salt thereof, in which L isother than a covalent bond or a bivalent, saturated or unsaturated,straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2 methylene unitsof L are independently and optionally replaced by —O—, —NR³—, —OC(O)—,—C(O)O—, —C(O)—, —NR³S(O)₂—, —S(O)₂NR³—, —N(R)C(O)—, —C(O)N(R)—, or—NR³C(O)O— when Ring A is

and X¹ is —C(O)—, Ring A is

and X² is

Ring A is

and X² is

Ring A is

Ring A is

and X¹ is —C(O)—or —CH₂—, or Ring A is

and X² is

and wherein the compound is other than a compound listed in Table 2.

As defined generally above, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from

In some embodiments, Ring A is other than

In some embodiments, Ring A is other than

In some embodiments, the compound is other than

In some embodiments, Ring A is selected from

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined generally above, each of X¹ and X⁶ is independently abivalent moiety selected from a covalent bond, —O—, —S—, —CH₂—,—C(R¹)H—, —C(R¹)CF₃—, —C(R¹)₂—, —C(O)—, —C(NR¹)—, —C(S)—, —N(R¹)—,—Si(R¹)₂—, —P(O)(OR¹)—, —P(O)(R¹)—, —P(O)N(R¹)₂—, or

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—O—. In some embodiments, X¹ is —S—. In some embodiments, X¹ is —CH₂—.In some embodiments, X¹ is —C(R¹)H—. In some embodiments, X¹ is—C(R¹)CF₃—. In some embodiments, X¹ is —C(O)—. In some embodiments, X¹is —C(NR¹)—. In some embodiments, X¹ is —C(S)—. In some embodiments, X¹is —N(R¹)—. In some embodiments, X¹ is —Si(R¹)₂—. In some embodiments,X¹ is —P(O)(R¹)—. In some embodiments, X¹ is —P(O)(R¹)—. In someembodiments, X¹ is —P(O)N(R¹)₂—. In some embodiments, X¹ is

In some embodiments, X⁶ is a covalent bond. In some embodiments, X⁶ is—O—. In some embodiments, X⁶ is —S—. In some embodiments, X⁶ is —CH₂—.In some embodiments, X⁶ is —C(R¹)H—. In some embodiments, X⁶ is—C(R¹)CF₃—. In some embodiments, X⁶ is —C(O)—. In some embodiments, X⁶is —C(NR¹)—. In some embodiments, X⁶ is —C(S)—. In some embodiments, X⁶is —N(R¹)—. In some embodiments, X⁶ is —Si(R¹)₂—. In some embodiments,X⁶ is —P(O)(R¹)—. In some embodiments, X⁶ is —P(O)(R¹)—. In someembodiments, X⁶ is —P(O)N(R¹)₂—. In some embodiments, X⁶ is

In some embodiments, X¹ and X⁶ are each independently selected from —O—,—C(O)—, —C(S)—, —Si(R¹)₂—, —P(O)(R¹)—, or

In some embodiments, X¹ and X⁶ are each independently selected fromthose depicted in Table 1, below.

As defined generally above, X² is a trivalent moiety selected from

In some embodiments, X² is

In some embodiments, X² is

In some embodiments, X² is

In some embodiments, X² is

In some embodiments, X² is

In some embodiments, X² is

In some embodiments, X² is

In some embodiments, X² is selected from those depicted in Table 1,below.

As defined generally above, each of X³ and X⁴ is independently abivalent moiety selected from a covalent bond, —O—, —C(R)₂—, —CF₂—,—CHF—, —S—, —S(O)—, —S(O)₂—, —Si(R¹)₂—, —P(O)(R¹)—, or —N(R)—.

In some embodiments, X³ is a covalent bond. In some embodiments, X³ is—O—. In some embodiments, X³ is —C(R)₂—. In some embodiments, X³ is—CF₂—. In some embodiments, X³ is —CHF—. In some embodiments, X³ is —S—.In some embodiments, X³ is —S(O)—. In some embodiments, X³ is —S(O)₂—.In some embodiments, X³ is —Si(R¹)₂—. In some embodiments, X³ is—P(O)(R¹)—. In some embodiments, X³ is —N(R)—.

In some embodiments, X³ is selected from those depicted in Table 1,below.

In some embodiments, X⁴ is a covalent bond. In some embodiments, X⁴ is—O—. In some embodiments, X⁴ is —C(R)₂—. In some embodiments, X⁴ is—CF₂—. In some embodiments, X⁴ is —CHF—. In some embodiments, X⁴ is —S—.In some embodiments, X⁴ is —S(O)—. In some embodiments, X⁴ is —S(O)₂—.In some embodiments, X⁴ is —Si(R¹)₂—. In some embodiments, X⁴ is—P(O)(R¹)—. In some embodiments, X⁴ is —N(R)—.

In some embodiments, X⁴ is selected from those depicted in Table 1,below.

As defined generally above, X⁵ is a bivalent moiety selected from acovalent bond, —O—,

—S—, —CH₂—, —C(R¹)H—, —C(R¹)CF₃—, —C(R¹)₂—, —C(O)—, —C(NR¹)—, —C(S)—,—N(R¹)—, —Si(R¹)₂—, —P(O)(OR¹)—, —P(O)(R¹)—, —P(O)N(R¹)₂—, or

In some embodiments, X⁵ is a covalent bond. In some embodiments, X⁵ is—O—. In some embodiments, X⁵ is —S—. In some embodiments, X⁵ is —CH₂—.In some embodiments, X⁵ is —C(R¹)H—. In some embodiments, X⁵ is—C(R¹)CF₃—. In some embodiments, X⁵ is-C(O)—. In some embodiments, X⁵ is—C(NR¹)—. In some embodiments, X⁵ is —C(S)—. In some embodiments, X⁵ is—N(R¹)—. In some embodiments, X⁵ is —Si(R¹)₂—. In some embodiments, X⁵is —P(O)(R¹)—. In some embodiments, X⁵ is —P(O)(R¹)—. In someembodiments, X⁵ is —P(O)N(R¹)₂—. In some embodiments, X⁵ is

In some embodiments, X⁵ is selected from those depicted in Table 1,below.

As defined generally above, each R is independently hydrogen, deuterium,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 4-7 membered saturated or partially unsaturated heterocyclic ringhaving 1-2 heteroatoms independently selected from boron, nitrogen,oxygen, silicon, or sulfur, a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, a 7-13 membered saturated, partially unsaturated,bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur, and a 8-10 membered bicyclic heteroaryl ring having1-4 heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or two R groups on the same nitrogen are optionallytaken together with their intervening atoms to form a 4-8 memberedsaturated, partially unsaturated, or heteroaryl monocyclic ring having0-1 heteroatom, in addition to the nitrogen, independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, or a 7-13 memberedsaturated, partially unsaturated, bridged heterocyclic ring, or a spiroheterocyclic ring having 0-2 heteroatoms, in addition to the nitrogen,independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is deuterium.In some embodiments, R is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R is an optionally substituted phenyl. In someembodiments, R is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur.In some embodiments, R is an optionally substituted 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, R isan optionally substituted 7-13 membered saturated, partiallyunsaturated, bridged heterocyclic ring, or a spiro heterocyclic ringhaving 1-3 heteroatoms, independently selected from boron, nitrogen,oxygen, silicon, or sulfur. In some embodiments, R is an optionallysubstituted 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, two R groups on the samenitrogen are optionally taken together with their intervening atoms toform an optionally substituted 4-8 membered saturated, partiallyunsaturated, or heteroaryl monocyclic ring having 0-1 heteroatom, inaddition to the nitrogen, independently selected from boron, nitrogen,oxygen, silicon, or sulfur. In some embodiments, two R groups on thesame nitrogen are optionally taken together with their intervening atomsto form an optionally substituted 7-13 membered saturated, partiallyunsaturated, bridged heterocyclic ring, or a spiro heterocyclic ringhaving 0-2 heteroatoms, in addition to the nitrogen, independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined generally above, each R¹ is independently hydrogen,deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(R)₂,—P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)R₂, —Si(OH)₂R, —SiR₃, oran optionally substituted C₁₋₄ aliphatic, or R¹ and X¹ or X⁴ are takentogether with their intervening atoms to form a 5-7 membered saturated,partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or two R¹ groups on the same carbon are optionallytaken together with their intervening atoms to form a 3-6 membered spirofused ring or a 4-7 membered heterocyclic ring having 1-2 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,or two R¹ groups on adjacent carbon atoms are optionally taken togetherwith their intervening atoms to form a 3-7 membered saturated, partiallyunsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, or a 7-13 membered saturated, partially unsaturated,bridged heterocyclic ring, or a spiro heterocyclic ring having 1-3heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, or sulfur.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R¹ is halogen. In some embodiments, R¹is —CN. In some embodiments, R¹ is —OR. In some embodiments, R¹ is —SR.In some embodiments, R¹ is —S(O)R. In some embodiments, R¹ is —S(O)₂R.In some embodiments, R¹ is —N(R)₂. In some embodiments, R¹ is —Si(R)₃.In some embodiments, R¹ is —P(O)(R)₂. In some embodiments, R¹ is—P(O)(OR)₂. In some embodiments, R¹ is —P(O)(NR₂)OR. In someembodiments, R¹ is —P(O)(NR₂)₂. In some embodiments, R¹ is —Si(OH)R₂. Insome embodiments, R¹ is —Si(OH)₂R. In some embodiments, R¹ is anoptionally substituted C₁₋₄ aliphatic. In some embodiments, R¹ and X¹ orX⁴ are taken together with their intervening atoms to form a 5-7membered saturated, partially unsaturated, carbocyclic ring orheterocyclic ring having 1-3 heteroatoms, independently selected fromboron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, two R¹groups on the same carbon are optionally taken together with theirintervening atoms to form a 3-6 membered spiro fused ring or a 4-7membered heterocyclic ring having 1-2 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments,two R¹ groups on adjacent carbon atoms are optionally taken togetherwith their intervening atoms to form a 3-7 membered saturated, partiallyunsaturated, carbocyclic ring or heterocyclic ring having 1-3heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur. In some embodiments, two R¹ groups on adjacentcarbon atoms are optionally taken together with their intervening atomsto form a 7-13 membered saturated, partially unsaturated, bridgedheterocyclic ring, or a spiro heterocyclic ring having 1-3 heteroatoms,independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, R¹ is selected from hydrogen, halogen, —CN, —OR,—N(R)₂, or C₁₋₄ alkyl. In some embodiments, R¹ is selected fromhydrogen, halogen, —CN, or C₁₋₄ alkyl. In some embodiments, R¹ isfluoro. In some embodiments, two R¹ groups on the same carbon areoptionally taken together with their intervening atoms to form a 3- or4-membered spiro fused ring.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined generally above, each R² is independently hydrogen,deuterium, halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(OH)₂R, —Si(OH)(R)₂,—Si(R)₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)S(O)₂R, —N(R)S(O)₂NR₂, —P(O)(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR,—P(O)(NR₂)₂, optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur,optionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from boron, nitrogen, oxygen,silicon, or sulfur, optionally substituted 7-13 membered saturated,partially unsaturated, bridged heterocyclic ring, or a spiroheterocyclic ring having 1-3 heteroatoms, independently selected fromboron, nitrogen, oxygen, silicon, or sulfur; or a 8-10 membered bicyclicheteroaryl ring having 1-4 heteroatoms, independently selected fromboron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, R² is hydrogen. In some embodiments, R² isdeuterium. In some embodiments, R² is halogen. In some embodiments, R²is —CN. In some embodiments, R² is —NO₂. In some embodiments, R² is —OR.In some embodiments, R² is —SR. In some embodiments, R² is —N(R)₂. Insome embodiments, R² is —Si(OH)₂R. In some embodiments, R² is—Si(OH)(R)₂. In some embodiments, R² is —S(O)₂R. In some embodiments, R²is —S(O)₂N(R)₂. In some embodiments, R² is —S(O)R. In some embodiments,R² is —C(O)R. In some embodiments, R² is —C(O)OR. In some embodiments,R² is —C(O)NR₂. In some embodiments, R² is —C(O)N(R)OR. In someembodiments, R² is —OC(O)R. In some embodiments, R² is —OC(O)NR₂. Insome embodiments, R² is —N(R)C(O)OR. In some embodiments, R² is—N(R)C(O)R. In some embodiments, R² is —N(R)C(O)NR₂. In someembodiments, R² is —N(R)S(O)₂R. In some embodiments, R² is —Si(R)₃. Insome embodiments, R² is —P(O)(R)₂. —P(O)(OR)₂. In some embodiments, R²is —P(O)(NR₂)OR. In some embodiments, R² is —P(O)(NR₂)₂. In someembodiments, R² is an optionally substituted C₁₋₆ aliphatic. In someembodiments, R² is an optionally substituted phenyl. In someembodiments, R² is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur.In some embodiments, R² is an optionally substituted 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, R² isan optionally substituted 7-13 membered saturated, partiallyunsaturated, bridged heterocyclic ring, or a spiro heterocyclic ringhaving 1-3 heteroatoms, independently selected from boron, nitrogen,oxygen, silicon, or sulfur. In some embodiments, R² is an 8-10 memberedbicyclic heteroaryl ring having 1-4 heteroatoms, independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, R² is hydrogen, halogen, —CN, —NO₂, —OR, —SR,—N(R)₂, —C(O)R, —N(R)C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R,—OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R,optionally substituted C₁₋₆ aliphatic, optionally substituted phenyl, anoptionally substituted 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, or an optionallysubstituted 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrog boron, nitrogen, oxygen, silicon, orsulfur; wherein R is hydrogen, C₁₋₄ alkyl optionally substituted with 1,2, or 3 deuterium or halogen atoms, or phenyl.

In some embodiments, R² is hydrogen, halogen, —CN, —OR, —N(R)₂, —C(O)R,—N(R)C(O)R, —C(O)OR, —C(O)NR₂, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, C₁₋₆aliphatic optionally substituted with 1, 2, 3, 4, 5, or 6 deuterium orhalogen atoms, phenyl optionally substituted with 1, 2, or 3 halogen,C₁₋₄ alkyl, —OR, —N(R)₂, or —CN groups, 4-7 membered saturated orpartially unsaturated heterocyclic ring optionally substituted with acarbonyl or C₁₋₄ alkyl group and having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroarylring optionally substituted with 1, 2, or 3 halogen, C₁₋₄ alkyl, —OR,—N(R)₂, or —CN groups and having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; wherein R is hydrogen, C₁₋₄ alkyloptionally substituted with 1, 2, or 3 deuterium or halogen atoms, orphenyl.

In some embodiments, R² is C₁₋₄ aliphatic optionally substituted with 1,2, 3, 4, 5, or 6 deuterium or halogen atoms.

In some embodiments, R² is methyl. In some embodiments, R² is phenyl. Insome embodiments, R² is C₁₋₄ aliphatic optionally substituted with 1, 2,3, 4, 5, or 6 deuterium or halogen atoms. In some embodiments, R² is—C(O)Et. In some embodiments, R² is —C(O)t-Bu.

In some embodiments, R² is selected from those depicted in Table 1,below.

As defined generally above, L is a covalent bond or a bivalent,saturated or unsaturated, straight or branched C₁₋₆ hydrocarbon chain,wherein 1-2 methylene units of L are independently and optionallyreplaced by —O—, —NR³—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —Si(R)₂—,—P(O)(R¹)—, —P(O)(OR)—, —P(O)(NR₂)—, —S(O)—, —S(O)₂—, —NR³S(O)₂—,—S(O)₂NR³—, —NR³C(O)—, —C(O)NR³—, —OC(O)NR³—, —NR³C(O)O—,

provided that L is other than a covalent bond, —CH₂—, —C(O)O—,—C(O)OCH₂—, —CH₂C(O)—, —C(O)CH₂—, —N(R)C(O)—, —C(O)N(R)—, or —CH₂CH₂—when Ring A is

and X¹ is —C(O)— or Ring A is

and X² is

In some embodiments, L is a covalent bond. In some embodiments, L is abivalent, saturated or unsaturated, straight or branched C₁₋₆hydrocarbon chain. In some embodiments, L is a bivalent, saturated orunsaturated, straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2methylene units of L are independently and optionally replaced by —O—,—NR³—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —Si(R)₂—, —P(O)(R¹)—, —P(O)(OR)—,—P(O)(NR₂)—, —S(O)—, —S(O)₂—, —NR³S(O)₂—, —S(O)₂NR³—, —NR³C(O)—,—C(O)NR³—, —OC(O)NR³—, —NR³C(O)O—,

In some embodiments, L is other than a covalent bond, —CH₂—, —C(O)O—,—C(O)OCH₂—, —CH₂C(O)—, —C(O)CH₂—, —N(R)C(O)—, —C(O)N(R)—, or —CH₂CH₂—when Ring A is

and X¹ is —C(O)— or Ring A is

and X² is or

In some embodiments, L is a covalent bond or a bivalent, saturated,straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2 methylene unitsof L are independently and optionally replaced by —O—, —S—, —S(O)—,—S(O)₂—,

In some embodiments, L is a bivalent, saturated, straight C₁₋₆hydrocarbon chain. In some embodiments, L is a bivalent, saturated,straight C₁₋₃ hydrocarbon chain. In some embodiments, L is a bivalent,saturated, straight C₂₋₃ hydrocarbon chain. In some embodiments, L is—CH₂—, —O—, —S—, —N(R)—, —OCH₂—, —SCH₂—, —CH₂O—, —CH₂O—, —OCH₂O—,—SCH₂O—, —OCH₂S—, —SCH₂S—, —SCH₂OC(O)—, —N(R)CH₂O—, —OCH₂N(R)—,—OCH₂CH₂O—, —SCH₂CH₂O—, —OCH₂CH₂S—, or —SCH₂CH₂S—.

In some embodiments, L is —CH₂—. In some embodiments, L is —N(CH₃)C(O)—or —(O)CN(CH₃)—.

In some embodiments, L is other than a covalent bond or a bivalent,saturated or unsaturated, straight or branched C₁₋₆ hydrocarbon chain,wherein 1-2 methylene units of L are independently and optionallyreplaced by —O—, —NR³—, —OC(O)—, —C(O)O—, —C(O)—, —NR³S(O)₂—,—S(O)₂NR³—, —N(R)C(O)—, —C(O)N(R)—, or —NR³C(O)O— when Ring A is

and X¹ is —C(O)—, Ring A is

and X² is

Ring A is

and X² is

Ring A is

Ring A is

and X¹ is —C(O)— or —CH₂—, or Ring A is

and X² is

In some embodiments, L is other than a covalent bond when Ring A is

and X¹ is —C(O)—. In some embodiments, L is other than a covalent bondwhen Ring A is

and X² is

In some embodiments, L is other than a covalent bond when Ring A is

and X² is

In some embodiments, L is other than a covalent bond when Ring A is

In some embodiments, L is other than a covalent bond when Ring A is

and X¹ is —C(O)— or —CH₂—. In some embodiments, L is other than acovalent bond when Ring A is

and X₂ is

In some embodiments, L is other than a bivalent, saturated orunsaturated, straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2methylene units of L are independently and optionally replaced by —O—,—NR³—, —OC(O)—, —C(O)O—, —C(O)—, —NR³S(O)₂—, —S(O)₂NR³—, —N(R)C(O)—,—C(O)N(R)—, or —NR³C(O)— when Ring A is

and X¹ is —C(O)—. In some embodiments, L is other than a bivalent,saturated or unsaturated, straight or branched C₁₋₆ hydrocarbon chain,wherein 1-2 methylene units of L are independently and optionallyreplaced by —O—, —NR³—, —OC(O)—, —C(O)O—, —C(O)—, —NR³S(O)₂—,—S(O)₂NR³—, —N(R)C(O)—, —C(O)N(R)—, or —NR³C(O)O— when Ring A is

and X² is

In some embodiments, L is other than a bivalent, saturated orunsaturated, straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2methylene units of L are independently and optionally replaced by —O—,—NR³—, —OC(O)—, —C(O)O—, —C(O)—, —NR³S(O)₂—, —S(O)₂NR³—, —N(R)C(O)—,—C(O)N(R)—, or —NR³C(O)O— when Ring A is

and X² is

In some embodiments, L is other than a bivalent, saturated orunsaturated, straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2methylene units of L are independently and optionally replaced by —O—,—NR³—, —OC(O)—, —C(O)O—, —C(O)—, —NR³(O)₂—, —S(O)₂NR³—, —N(R)C(O)—,—C(O)N(R)—, or —NR³C(O)O— when Ring A is

In some embodiments, L is other than a bivalent, saturated orunsaturated, straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2methylene units of L are independently and optionally replaced by —O—,—NR³—, —OC(O)—, —C(O)O—, —C(O)—, —NR³S(O)₂—, —S(O)₂NR³—, —N(R)C(O)—,—C(O)N(R)—, or —NR³C(O)O— when Ring A is

and X¹ is —C(O)— or —CH₂—. In some embodiments, L is other than abivalent, saturated or unsaturated, straight or branched C₁₋₆hydrocarbon chain, wherein 1-2 methylene units of L are independentlyand optionally replaced by —O—, —NR³—, —OC(O)—, —C(O)O—, —C(O)—,—NR³S(O)₂—, —S(O)₂NR³—, —N(R)C(O)—, —C(O)N(R)—, or —NR³C(O)O— when RingA is

and X² is

In some embodiments, L is selected from those depicted in Table 1,below.

As defined generally above, each R³ is independently hydrogen,deuterium, or an optionally substituted C₁₋₄ aliphatic.

In some embodiments, R³ is hydrogen. In some embodiments, R³ isdeuterium. In some embodiments, R³ is an optionally substituted C₁₋₄aliphatic.

In some embodiments, R³ is methyl.

In some embodiments, R³ is selected from those depicted in Table 1,below.

As defined generally above, Ring B is a 3 to 7-membered saturated orpartially unsaturated carbocyclic ring, phenyl, 8-10 membered bicycliccarbocyclic aromatic ring, 4-7 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur, 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, 7-13 membered saturated, partiallyunsaturated, bridged heterocyclic ring, or a spiro heterocyclic ringhaving 1-3 heteroatoms, independently selected from boron, nitrogen,oxygen, silicon, or sulfur, or a 8-10 membered bicyclic heteroaryl ringhaving 1-4 heteroatoms, independently selected from boron, nitrogen,oxygen, silicon, or sulfur; wherein Ring B is optionally furthersubstituted with 1-2 oxo groups.

In some embodiments, Ring B is a 3 to 7-membered saturated or partiallyunsaturated carbocyclic ring. In some embodiments, Ring B is phenyl. Insome embodiments, Ring B is an 8-10 membered bicyclic carbocyclicaromatic ring. In some embodiments, Ring B is a 4-7 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from boron, nitrogen, oxygen, silicon, or sulfur.In some embodiments, Ring B is a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring B is a 7-13 membered saturated, partiallyunsaturated, bridged heterocyclic ring, or a spiro heterocyclic ringhaving 1-3 heteroatoms, independently selected from boron, nitrogen,oxygen, silicon, or sulfur. In some embodiments, Ring B is a 8-10membered bicyclic heteroaryl ring having 1-4 heteroatoms, independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur. In someembodiments, Ring B is optionally further substituted with 1-2 oxogroups.

In some embodiments, Ring B is selected from

phenyl, pyridinyl, pyrimidinyl,

triazolyl,

In some embodiments,

is selected from

In some embodiments,

is selected from

In some embodiments, Ring B is selected from those depicted in Table 1,below.

As defined generally above, m is 0, 1, 2, 3 or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments, m is 1-3, 1-2, or 0-1.

In some embodiments, m is selected from those depicted in Table 1,below.

As defined generally above, n is 0, 1, 2, 3 or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In some embodiments, n is 0-3, 0-2, 0-1, 1-3, or 1-2.

In some embodiments, n is selected from those depicted in Table 1,below.

In some embodiments, Ring A is selected from

and L is a covalent bond or a bivalent, saturated, straight or branchedC₁₋₆ hydrocarbon chain, wherein 1-2 methylene units of L areindependently and optionally replaced by —O—, —S—, —S(O)—, —S(O)₂—,

In some embodiments, Ring A is selected from

and L is a bivalent, saturated, straight or branched C₁₋₆ hydrocarbonchain, wherein 1-2 methylene units of L are independently replaced by—O—, —S—, —S(O)—, —S(O)₂—,

In some embodiments, X² is a trivalent moiety selected from

In some embodiments, the present invention provides a compound ofFormula I-a or I-b:

or a pharmaceutically acceptable salt thereof, wherein:

-   each R¹ is independently hydrogen, deuterium, halogen, —CN, —OR,    —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,    —Si(OH)R₂, —Si(OH)₂R, —SiR₃, or an optionally substituted C₁₋₄    aliphatic; or    -   two R¹ groups on the same carbon are optionally taken together        with their intervening atoms to form a 3-6 membered spiro fused        ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;    -   two R¹ groups on adjacent carbon atoms are optionally taken        together with their intervening atoms to form a 3-7 membered        saturated, partially unsaturated, carbocyclic ring or        heterocyclic ring having 1-3 heteroatoms independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 1-3 heteroatoms,        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;-   each R is independently hydrogen, deuterium, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 7-13 membered saturated, partially    unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring    having 1-3 heteroatoms, independently selected from boron, nitrogen,    oxygen, silicon, or sulfur, and a 8-10 membered bicyclic heteroaryl    ring having 1-4 heteroatoms, independently selected from boron,    nitrogen, oxygen, silicon, or sulfur; or    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-8 membered saturated,        partially unsaturated, or heteroaryl monocyclic ring having 0-1        heteroatom, in addition to the nitrogen, independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 0-2 heteroatoms, in        addition to the nitrogen, independently selected from boron,        nitrogen, oxygen, silicon, or sulfur;-   each R² is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OR, —SR, —NR₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂,    —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —N(R)S(O)₂NR₂,    —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, optionally substituted C₁₋₆    aliphatic, optionally substituted phenyl, optionally substituted 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, optionally substituted 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from boron,    nitrogen, oxygen, silicon, or sulfur, optionally substituted 7-13    membered saturated, partially unsaturated, bridged heterocyclic    ring, or a spiro heterocyclic ring having 1-3 heteroatoms,    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur;-   Ring B is selected from a 3 to 7-membered saturated or partially    unsaturated carbocyclic ring, phenyl, 8-10 membered bicyclic    carbocyclic aromatic ring, 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, 7-13    membered saturated, partially unsaturated, bridged heterocyclic    ring, or a spiro heterocyclic ring having 1-3 heteroatoms,    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur; wherein Ring B is optionally further substituted    with 1-2 oxo groups;-   m is 0, 1, 2, 3, or 4; and-   n is 0, 1, 2, 3, or 4

In some embodiments, the present invention provides a compound ofFormula I-b wherein said compound is other than

In some embodiments, the present invention provides a compound ofFormula I-b′ or I-b′:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,Ring B, m, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula I-c, I-d, I-e, or I-f:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,Ring B, m, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, Ring B is selected from phenyl, an 8-10 memberedbicyclic carbocyclic aromatic ring, a 5-6-membered heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, Ring B is selected from

triazolyl

In some embodiments, n is 1, 2, or 3.

In some embodiments, the present invention provides a compound ofFormula I-g, I-h, I-i, I-j, I-k, I-l, or I-m:

or a pharmaceutically acceptable salt thereof, wherein:

-   each R¹ is independently hydrogen, deuterium, halogen, —CN, —OR,    —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,    —Si(OH)R₂, —Si(OH)₂R, —SiR₃, or an optionally substituted C₁₋₄    aliphatic; or    -   two R¹ groups on the same carbon are optionally taken together        with their intervening atoms to form a 3-6 membered spiro fused        ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;    -   two R¹ groups on adjacent carbon atoms are optionally taken        together with their intervening atoms to form a 3-7 membered        saturated, partially unsaturated, carbocyclic ring or        heterocyclic ring having 1-3 heteroatoms independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 1-3 heteroatoms,        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;-   each R is independently hydrogen, deuterium, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 7-13 membered saturated, partially    unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring    having 1-3 heteroatoms, independently selected from boron, nitrogen,    oxygen, silicon, or sulfur, and a 8-10 membered bicyclic heteroaryl    ring having 1-4 heteroatoms, independently selected from boron,    nitrogen, oxygen, silicon, or sulfur; or    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-8 membered saturated,        partially unsaturated, or heteroaryl monocyclic ring having 0-1        heteroatom, in addition to the nitrogen, independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 0-2 heteroatoms, in        addition to the nitrogen, independently selected from boron,        nitrogen, oxygen, silicon, or sulfur;-   each R² is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OR, —SR, —NR₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂,    —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —N(R)S(O)₂NR₂,    —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, optionally substituted C₁₋₆    aliphatic, optionally substituted phenyl, optionally substituted 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, optionally substituted 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from boron,    nitrogen, oxygen, silicon, or sulfur, optionally substituted 7-13    membered saturated, partially unsaturated, bridged heterocyclic    ring, or a spiro heterocyclic ring having 1-3 heteroatoms,    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur;-   Ring B is selected from a 3 to 7-membered saturated or partially    unsaturated carbocyclic ring, phenyl, 8-10 membered bicyclic    carbocyclic aromatic ring, 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, 7-13    membered saturated, partially unsaturated, bridged heterocyclic    ring, or a spiro heterocyclic ring having 1-3 heteroatoms,    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur; wherein Ring B is optionally further substituted    with 1-2 oxo groups;-   m is 0, 1, 2, 3, or 4; and-   n is 0, 1, 2, 3, or 4

In some embodiments, the present invention provides a compound ofFormula I-g′, I-j′, I-k′, or I-′:

or a pharmaceutically acceptable salt thereof, wherein:

-   each of X⁵ and X⁶ is independently a bivalent moiety selected from a    covalent bond, —O—, —S—, —C(R¹)CF₃—, —C(R¹)₂—, —C(O)—, —N(R¹)—,    —C(NR¹)—, —C(S)—, —Si(R¹)₂—, —P(O)(R¹)—, —P(O)(OR¹)—, —P(O)N(R¹)₂—,    or

-   X³ is a bivalent moiety selected from a covalent bond, —O—, —S—,    —C(R¹)F—, —CF₂—, —C(R¹)₂—, —S(O)—, —S(O)₂—, —Si(R¹)₂—, —P(O)(R¹)—,    or —N(R)—;-   each R is independently hydrogen, deuterium, or an optionally    substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-2 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, a 7-13 membered saturated, partially    unsaturated, bridged heterocyclic ring, or a spiro heterocyclic ring    having 1-3 heteroatoms, independently selected from boron, nitrogen,    oxygen, silicon, or sulfur, and a 8-10 membered bicyclic heteroaryl    ring having 1-4 heteroatoms, independently selected from boron,    nitrogen, oxygen, silicon, or sulfur; or    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-8 membered saturated,        partially unsaturated, or heteroaryl monocyclic ring having 0-1        heteroatom, in addition to the nitrogen, independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 0-2 heteroatoms, in        addition to the nitrogen, independently selected from boron,        nitrogen, oxygen, silicon, or sulfur;-   each R¹ is independently hydrogen, deuterium, halogen, —CN, —OR,    —SR, —S(O)R, —S(O)₂R, —N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,    —Si(OH)R₂, —Si(OH)₂R, —SiR₃, or an optionally substituted C₁₋₄    aliphatic; or    -   two R¹ groups on the same carbon are optionally taken together        with their intervening atoms to form a 3-6 membered spiro fused        ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;    -   two R¹ groups on adjacent carbon atoms are optionally taken        together with their intervening atoms to form a 3-7 membered        saturated, partially unsaturated, carbocyclic ring or        heterocyclic ring having 1-3 heteroatoms independently selected        from boron, nitrogen, oxygen, silicon, or sulfur, or a 7-13        membered saturated, partially unsaturated, bridged heterocyclic        ring, or a spiro heterocyclic ring having 1-3 heteroatoms,        independently selected from boron, nitrogen, oxygen, silicon, or        sulfur;-   each R² is independently hydrogen, deuterium, halogen, —CN, —NO₂,    —OR, —SR, —NR₂, —Si(OH)₂R, —Si(OH)(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂,    —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,    —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, —N(R)S(O)₂R, —N(R)S(O)₂NR₂,    —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, optionally substituted C₁₋₆    aliphatic, optionally substituted phenyl, optionally substituted 4-7    membered saturated or partially unsaturated heterocyclic ring having    1-3 heteroatoms independently selected from boron, nitrogen, oxygen,    silicon, or sulfur, optionally substituted 5-6 membered heteroaryl    ring having 1-4 heteroatoms independently selected from boron,    nitrogen, oxygen, silicon, or sulfur, optionally substituted 7-13    membered saturated, partially unsaturated, bridged heterocyclic    ring, or a spiro heterocyclic ring having 1-3 heteroatoms,    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur;-   L is a covalent bond or a bivalent, saturated or unsaturated,    straight or branched C₁₋₆ hydrocarbon chain, wherein 1-2 methylene    units of L are independently and optionally replaced by —O—, —NR³—,    —S—, —OC(O)—, —C(O)O—, —C(O)—, —Si(R¹)₂—, —P(O)(R¹)—, —P(O)(OR)—,    —P(O)(NR₂)—, —S(O)—, —S(O)₂—, —NR³S(O)₂—, —S(O)₂NR³—, —NR³C(O)—,    —C(O)NR³—, —OC(O)NR³—, —NR³C(O)O—,

-   each R³ is independently hydrogen, deuterium, or optionally    substituted C₁₋₄ aliphatic;-   Ring B is selected from a 3 to 7-membered saturated or partially    unsaturated carbocyclic ring, phenyl, 8-10 membered bicyclic    carbocyclic aromatic ring, 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-2 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from boron, nitrogen, oxygen, silicon, or sulfur, 7-13    membered saturated, partially unsaturated, bridged heterocyclic    ring, or a spiro heterocyclic ring having 1-3 heteroatoms,    independently selected from boron, nitrogen, oxygen, silicon, or    sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4    heteroatoms, independently selected from boron, nitrogen, oxygen,    silicon, or sulfur; wherein Ring B is optionally further substituted    with 1-2 oxo groups;-   m is 0, 1, 2, 3, or 4; and-   n is 0, 1, 2, 3, or 4.

In some embodiments, the present invention provides a compound ofFormula I-k or I-k′ wherein said compound is other than

In some embodiments, a provided compound of the invention is selectedfrom one of those in Table 1, below, or a pharmaceutically acceptablesalt thereof.

TABLE 1 Exemplary Compounds Compound Number Structure I-1 

I-2 

I-3 

I-4 

I-5 

I-6 

I-7 

I-8 

I-9 

I-10 

I-11 

I-12 

I-13 

I-14 

I-15 

I-16 

I-17 

I-18 

I-19 

I-20 

I-21 

I-22 

I-23 

I-24 

I-25 

I-26 

I-27 

I-28 

I-29 

I-30 

I-31 

I-32 

I-33 

I-34 

I-35 

I-36 

I-37 

I-38 

I-39 

I-40 

I-41 

I-42 

I-43 

I-44 

I-45 

I-46 

I-47 

I-48 

I-49 

I-50 

I-51 

I-52 

I-53 

I-54 

I-55 

I-56 

I-57 

I-58 

I-59 

I-60 

I-61 

I-62 

I-63 

I-64 

I-65 

I-66 

I-67 

I-68 

I-69 

I-70 

I-71 

I-72 

I-73 

I-74 

I-75 

I-76 

I-77 

I-78 

I-79 

I-80 

I-81 

I-82 

I-83 

I-84 

I-85 

I-86 

I-87 

I-88 

I-89 

I-90 

I-91 

I-92 

I-93 

I-94 

I-95 

I-96 

I-97 

I-98 

I-99 

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

In some embodiments, the present invention provides a compound selectedfrom any of those depicted in Table 1, above, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, a disclosed method employs a compound set forth inTable 1, above, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I is other than those inTable 2, below, or a pharmaceutically acceptable salt thereof.

TABLE 2 Exemplary Excluded Compounds

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably bind CRBN, or a mutant thereof, ina biological sample or in a patient. In certain embodiments, the amountof compound in compositions of this invention is such that is effectiveto measurably bind CRBN, or a mutant thereof, in a biological sample orin a patient. In certain embodiments, a composition of this invention isformulated for administration to a patient in need of such composition.In some embodiments, a composition of this invention is formulated fororal administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an active metabolite or residue thereof.

As used herein, the term “active metabolite or residue thereof” meansthat a metabolite or residue thereof is also a binder of CRBN, or amutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of thecompound can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for themodulation of CRBN. In some embodiments the protein complex bound by thecompounds and methods of the invention comprises CRBN.

Cereblon is a protein that in humans is encoded by the CRBN gene. CRBNorthologs are highly conserved from plants to humans, which underscoresits physiological importance. Cereblon forms an E3 ubiquitin ligasecomplex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A),and regulator of cullins 1 (ROC1). This complex ubiquitinates a numberof other proteins. Through a mechanism which has not been completelyelucidated, cereblon ubquitination of target proteins results inincreased levels of fibroblast growth factor 8 (FGF8) and fibroblastgrowth factor 10 (FGF10). FGF8 in turn regulates a number ofdevelopmental processes, such as limb and auditory vesicle formation.The net result is that this ubiquitin ligase complex is important forlimb outgrowth in embryos. In the absence of cereblon, DDB1 forms acomplex with DDB2 that functions as a DNA damage-binding protein.

Accordingly, compounds that bind CRBN are beneficial, especially thosewith selectivity over other E3 ligases. Such compounds should deliver apharmacological response that favorably treats one or more of theconditions described herein without the side-effects associated with thebinding of other E3 ligases.

Even though CRBN ligands are known in the art, there is a continuingneed to provide novel ligands having more effective or advantageouspharmaceutically relevant properties. For example, compounds withincreased activity, selectivity over other E3 ligases, and ADMET(absorption, distribution, metabolism, excretion, and/or toxicity)properties. Thus, in some embodiments, the present invention providesbinders of CRBN which show selectivity over other E3 ligases.

The activity of a compound utilized in this invention as an binder ofCRBN, or a mutant thereof, may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine the subsequentfunctional consequences, or activity of activated CRBN, or a mutantthereof. Alternate in vitro assays quantitate the ability of thecompound to bind to CRBN. Compound binding may be measured byradiolabeling the compound prior to binding, isolating the compound/CRBNcomplex and determining the amount of radiolabel bound. Alternatively,compound binding may be determined by running a competition experimentwhere new compounds are incubated with CRBN bound to known radioligands.Representative in vitro and in vivo assays useful in assaying a CRBNbinder include those described and disclosed in, Boichenko et al. J.Med. Chem. (2016) 59, 770-774 and Iconomou and Saunders BiochemicalJournal (2016) 473, 4083-4101, each of which is herein incorporated byreference in its entirety. Detailed conditions for assaying a compoundutilized in this invention as a binder of CRBN, or a mutant thereof, areset forth in the Examples below.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are binders of CRBN and are therefore useful fortreating one or more disorders associated with activity of CRBN ormutants thereof. Thus, in certain embodiments, the present inventionprovides a method for treating a CRBN-mediated disorder comprising thestep of administering to a patient in need thereof a compound of thepresent invention, or pharmaceutically acceptable composition thereof.

As used herein, the term “CRBN-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which CRBN or a mutant thereof is known to play a role.Accordingly, another embodiment of the present invention relates totreating or lessening the severity of one or more diseases in whichCRBN, or a mutant thereof, is known to play a role. Such CRBN-mediateddisorders include but are not limited to proliferative disorders,neurological disorders and disorders associated with transplantation.

In some embodiments, the present invention provides a method fortreating one or more disorders, wherein the disorders are selected fromproliferative disorders, neurological disorders and disorders associatedwith transplantation, said method comprising administering to a patientin need thereof, a pharmaceutical composition comprising an effectiveamount of a compound of the present invention, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the disorder is a proliferative disorder. In someembodiments, the proliferative disorder is a hematological cancer. Insome embodiments, the proliferative disorder is a leukemia. In someembodiments, the proliferative disorder is a leukemia selected from thegroup consisting of anemia, acute leukemia, acute lymphoblastic leukemia(ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia,acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), adultacute basophilic leukemia, adult acute eosinophilic leukemia, adultacute megakaryoblastic leukemia, adult acute minimally differentiatedmyeloid leukemia, adult acute monoblastic leukemia, adult acutemonocytic leukemia, adult acute myeloblastic leukemia with maturation,adult acute myeloblastic leukemia without maturation, adult acutemyeloid leukemia with abnormalities, adult acute myelomonocyticleukemia, adult erythroleukemia, adult pure erythroid leukemia,secondary acute myeloid leukemia, untreated adult acute myeloidleukemia, adult acute myeloid leukemia in remission, adult acutepromyelocytic leukemia with PML-RARA, alkylating agent-related acutemyeloid leukemia, prolymphocytic leukemia, and chronic myelomonocyticleukemia.

In some embodiments, the proliferative disorder is a lymphoma. In someembodiments, the proliferative disorder is a lymphoma selected from thegroup consisting of adult grade III lymphomatoid granulomatosis, adultnasal type extranodal NK/T-cell lymphoma, anaplastic large celllymphoma, angioimmunoblastic T-cell lymphoma, cutaneous B-Cellnon-Hodgkin lymphoma, extranodal marginal zone lymphoma ofmucosa-associated lymphoid tissue, hepatosplenic T-cell lymphoma,intraocular lymphoma, lymphomatous involvement of non-cutaneousextranodal site, mature T-cell and NK-cell non-Hodgkin lymphoma, nodalmarginal zone lymphoma, post-transplant lymphoproliferative disorder,recurrent adult Burkitt lymphoma, recurrent adult diffuse large celllymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adultdiffuse small cleaved cell lymphoma, recurrent adult grade IIIlymphomatoid granulomatosis, recurrent adult immunoblastic lymphoma,recurrent adult lymphoblastic lymphoma, recurrent adult T-cellleukemia/lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma,recurrent grade 1 follicular lymphoma, recurrent grade 2 follicularlymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle celllymphoma, recurrent marginal zone lymphoma, recurrent mycosis fungoidesand Sezary syndrome, recurrent small lymphocytic lymphoma, refractorychronic lymphocytic leukemia, refractory hairy cell leukemia, Richtersyndrome, small intestinal lymphoma, splenic marginal zone lymphoma,T-cell large granular lymphocyte leukemia, testicular lymphoma,Waldenstrom macroglobulinemia, adult T-cell leukemia-lymphoma,peripheral T-cell lymphoma, B-cell lymphoma, Hodgkin's disease,cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, MALT lymphoma,mantle cell lymphoma, non-Hodgkins lymphoma, central nervous systemlymphoma, refractory primary-cutaneous large B-cell lymphoma (Leg-type),relapsed or refractory chronic lymphocytic leukemia, refractory anemia,refractory anemia with excess blasts, refractory anemia with ringedsideroblasts, refractory cytopenia with multilineage dysplasia, andsecondary myelodysplastic syndromes.

In some embodiments, the disorder is a neurological disorder. In someembodiments, the neurological disorder is Alzheimer's disease.

In some embodiments, the disorder is associated with transplantation. Insome embodiments the disorder associated with transplantation istransplant rejection, or graft versus host disease.

In some embodiments, the proliferative disorder is a cancer or tumor. Insome embodiments, the proliferative disorder is a cancer or tumorselected from the group consisting of head and neck cancer, livercancer, hormone-refractory prostate cancer, kidney cancer, smallintestine cancer, glioblastoma, non-small cell lung cancer, ovariancancer, endometrial cancer, esophageal cancer, colon cancer, lungcancer, brain and central nervous system tumors, gastrointestinalcarcinoid tumor, islet cell tumor, and childhood solid tumor.

In some embodiments, the proliferative disorder is a myeloma. In someembodiments, the proliferative disorder is a multiple myeloma.

In some embodiments, the proliferative disorder is a myeloma selectedfrom the group consisting of refractory multiple myeloma, stage Imultiple myeloma, stage II multiple myeloma, stage III multiple myeloma,smoldering plasma cell myeloma, and plasma cell myeloma.

In some embodiments, the proliferative disorder is selected from thegroup consisting of hepatocellular carcinoma, melanoma, malignantmelanoma, thyroid neoplasms, urinary bladder neoplasms, amyotrophiclateral sclerosis (ALS), sickle cell anemia, ankylosing spondylitis,arachnoiditis, arterivenous malformation, and hereditary hemorrhagictelangiectasia.

In some embodiments, the disorder is selected from the group consistingof AIDS-related Kaposi sarcoma, amyloidosis, hematochezia, melena,autism, burning mouth syndrome associated with HIV infection,hepatocellular carcinoma, non-small-cell lung carcinoma, central nervoussystem neoplasms, medulloblastoma, chronic myeloproliferative disorders,secondary myelofibrosis, chronic pancreatitis, chronic prostatitis,complex regional pain syndrome (RSD), Type 1 complex regional painsyndrome, Crohn's disease, cutaneous lupus erythematosus (CLE), discoidlupus erythematosus, endometriosis, neoplastic syndrome,gastrointestinal hemorrhage, gastrointestinal vascular malformation,hepatitis C, high grade squamous intra-epithelial lesion (HSIL), HIVwasting syndrome, HIV-associated mycobacterium infections,HIV-associated tuberculosis, HIV-associated aphthous stomatitis,HIV-associated avium-intracellulare infection, idiopathic pulmonaryfibrosis (IPF), Langerhans cell histiocytosis (LCH), histiocytosis,Erdheim-Chester disease, histiocytic light chain deposition disease,myelofibrosis, myeloproliferative neoplasms, neurofibromatosis type 1,recurrent central nervous system neoplasm, recurrent childhood brainstem glioma, recurrent childhood visual pathway glioma, refractorycentral nervous system neoplasm, nonmalignant monoclonal gammopathy ofundetermined significance (MGUS), primary amyloidosis, primarymyelofibrosis, primary sclerosing cholangitis, plaque-type psoriasis,pulmonary fibrosis, radiation injuries, radiculopathy, recurrent uterinecorpus sarcoma, uterine carcinosarcoma, refractory epilepsy,sarcoidosis, systemic scleroderma, systemic sclerosis, Sjogren'sSyndrome, xerostomia, soft tissue sarcoma, thalassemia, and uveitis.

In some embodiments, compounds of the present invention bind to CRBN,altering the specificity of the complex to induce the ubiquitination anddegradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factorsessential for multiple myeloma growth.

In some embodiments, compounds of the present invention bind to CRBN,altering the specificity of the complex to induce the ubiquitination anddegradation of a complex-associated protein selected from the groupconsisting of A1BG, A1CF, A2M, A2ML1, A3GALT2, A4GALT, A4GNT, AAAS,AACS, AADAC, AADACL2, AADACL3, AADACL4, AADAT, AAED1, AAGAB, AAK1,AAMDC, AAMP, AANAT, AAR2, AARD, AARS, AARS2, AARSD1, AASDH, AASDHPPT,AASS, AATF, AATK, AATK-AS1, ABAT, ABCA1, ABCA10, ABCA12, ABCA13, ABCA2,ABCA3, ABCA4, ABCA5, ABCA6, ABCA7, ABCA8, ABCA9, ABCB1, ABCB10, ABCB11,ABCB4, ABCB5, ABCB6, ABCB7, ABCB8, ABCB9, ABCC1, ABCC10, ABCC11, ABCC12,ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCC8, ABCC9, ABCD1, ABCD2, ABCD3,ABCD4, ABCE1, ABCF1, ABCF2, ABCF3, ABCG1, ABCG2, ABCG4, ABCG5, ABCG8,ABHD1, ABHD10, ABHD11, ABHD12, ABHD12B, ABHD13, ABHD14A, ABHD14A-ACY1,ABHD14B, ABHD15, ABHD16A, ABHD16B, ABHD17A, ABHD17B, ABHD17C, ABHD18,ABHD2, ABHD3, ABHD4, ABHD5, ABHD6, ABHD8, ABI1, ABI2, ABI3, ABI3BP,ABL1, ABL2, ABLIM1, ABLIM2, ABLIM3, ABO, ABR, ABRA, ABRACL, ABRAXAS1,ABRAXAS2, ABT1, ABTB1, ABTB2, AC001226.2, AC002094.3, AC002115.2,AC002310.4, AC002310.5, AC002429.2, AC002985.1, AC002996.1, AC003002.1,AC003002.2, AC003002.3, AC003002.4, AC003005.1, AC003006.1, AC003688.1,AC004076.1, AC004080.3, AC004223.3, AC004233.2, AC004556.1, AC004691.2,AC004706.4, AC004754.1, AC004805.1, AC004832.3, AC004922.1, AC004997.1,AC005020.2, AC005041.1, AC005154.6, AC005258.1, AC005324.3, AC005324.4,AC005520.1, AC005551.1, AC005670.2, AC005697.1, AC005702.2, AC005726.2,AC005779.2, AC005832.4, AC005833.1, AC005833.3, AC005837.2, AC005841.2,AC005885.1, AC005943.1, AC006030.1, AC006254.1, AC006269.1, AC006449.4,AC006486.1, AC006538.2, AC006978.2, AC007040.2, AC007192.1, AC007240.1,AC007325.1, AC007325.2, AC007325.4, AC007326.4, AC007375.2, AC007383.6,AC007537.5, AC007731.5, AC007906.2, AC007998.2, AC008073.3, AC008162.2,AC008393.2, AC008403.1, AC008481.3, AC008537.1, AC008560.1, AC008575.1,AC008575.2, AC008687.1, AC008687.4, AC008687.8, AC008695.1, AC008735.6,AC008750.8, AC008758.1, AC008758.4, AC008758.5, AC008758.6, AC008763.2,AC008763.3, AC008764.1, AC008764.4, AC008770.2, AC008770.3, AC008878.1,AC008878.2, AC008878.3, AC008982.1, AC008982.3, AC009014.1, AC009086.2,AC009119.2, AC009122.1, AC009133.6, AC009163.2, AC009163.4, AC009286.3,AC009336.2, AC009477.2, AC009690.1, AC009690.3, AC009779.3, AC010132.3,AC010255.3, AC010319.2, AC010323.1, AC010325.1, AC010326.2, AC010327.1,AC010422.3, AC010422.5, AC010422.6, AC010463.1, AC010487.3, AC010522.1,AC010531.1, AC010542.3, AC010547.4, AC010547.5, AC010615.4, AC010616.1,AC010619.1, AC010646.1, AC010724.2, AC011005.1, AC011043.1, AC011043.2,AC011195.2, AC011295.1, AC011346.1, AC011448.1, AC011452.1, AC011455.3,AC011455.4, AC011462.1, AC011473.4, AC011479.1, AC011498.4, AC011499.1,AC011511.1, AC011511.4, AC011530.1, AC011604.2, AC011841.1, AC012184.2,AC012254.2, AC012309.1, AC012314.1, AC012314.10, AC012314.11,AC012314.12, AC012314.4, AC012314.5, AC012314.6, AC012314.8, AC012531.3,AC012651.1, AC013269.1, AC013271.1, AC013394.1, AC013470.2, AC015688.5,AC015802.6, AC015813.2, AC017081.3, AC017081.4, AC017081.5, AC017083.4,AC018512.1, AC018523.2, AC018554.3, AC018630.6, AC018709.1, AC018755.2,AC018793.1, AC018793.2, AC018793.3, AC018793.4, AC018793.5, AC019117.3,AC020636.2, AC020909.1, AC020914.1, AC020915.1, AC020915.2, AC020915.6,AC020922.1, AC020934.3, AC021072.1, AC022016.2, AC022167.5, AC022335.1,AC022384.1, AC022400.6, AC022826.2, AC023055.1, AC023491.2, AC023509.3,AC024592.3, AC024940.1, AC024940.6, AC025165.3, AC025263.2, AC025283.2,AC025287.4, AC025594.2, AC026369.8, AC026398.1, AC026461.4, AC026464.1,AC026464.3, AC026464.4, AC026786.1, AC026954.2, AC027796.3, AC034102.2,AC036214.3, AC037459.1, AC037482.2, AC037482.3, AC040162.1, AC040162.4,AC044810.8, AC046185.1, AC048338.1, AC051649.2, AC053481.5, AC055811.2,AC058822.1, AC064853.2, AC064853.3, AC064853.4, AC064853.5, AC064853.6,AC067968.1, AC068234.1, AC068533.4, AC068547.1, AC068580.4, AC068631.2,AC068775.1, AC068775.2, AC068790.8, AC068896.1, AC068946.1, AC068987.5,AC069257.3, AC069368.1, AC069503.2, AC069544.2, AC072022.1, AC073082.1,AC073111.3, AC073111.5, AC073264.3, AC073508.2, AC073610.2, AC073610.3,AC073612.1, AC073896.1, AC074143.1, AC078927.1, AC079325.2, AC079447.1,AC079594.2, AC083800.1, AC083902.2, AC084337.2, AC087289.3, AC087498.1,AC087632.1, AC090004.1, AC090227.1, AC090360.1, AC090527.2, AC090958.3,AC091167.3, AC091167.7, AC091167.8, AC091304.7, AC091491.1, AC091551.1,AC091959.3, AC091980.2, AC092017.3, AC092042.3, AC092073.1, AC092111.3,AC092143.1, AC092329.3, AC092442.1, AC092587.1, AC092647.5, AC092718.3,AC092718.8, AC092821.1, AC092824.3, AC092835.1, AC093155.3, AC093227.3,AC093423.3, AC093525.1, AC093525.2, AC093668.1, AC093762.1, AC093762.2,AC093762.3, AC093899.2, AC096582.3, AC096887.1, AC097372.1, AC097495.1,AC097637.1, AC097662.2, AC098484.3, AC098650.1, AC098850.4, AC099329.3,AC099489.1, AC099518.3, AC099811.2, AC099850.2, AC100868.1, AC104109.3,AC104151.1, AC104304.1, AC104452.1, AC104532.1, AC104534.3, AC104581.1,AC104581.3, AC104662.2, AC104836.1, AC105001.2, AC105052.1, AC106774.10,AC106774.5, AC106774.6, AC106774.7, AC106774.8, AC106774.9, AC106782.1,AC106886.5, AC107871.1, AC108488.2, AC108750.1, AC108941.2, AC109583.3,AC110275.1, AC112229.3, AC112484.1, AC113189.6, AC113189.9, AC113331.2,AC113554.2, AC114296.1, AC114490.2, AC115220.1, AC116366.3, AC116565.1,AC117457.1, AC118470.1, AC118553.2, AC119396.1, AC119674.2, AC120057.3,AC120114.5, AC124312.1, AC126755.2, AC127537.5, AC127537.6, AC127537.8,AC129492.3, AC131097.2, AC131160.1, AC133551.1, AC133555.3, AC134669.2,AC134772.2, AC135050.2, AC135068.1, AC135068.2, AC135068.3, AC135068.8,AC135178.2, AC135586.2, AC136352.3, AC136352.4, AC136428.1, AC136612.1,AC136616.1, AC136616.2, AC136616.3, AC137834.1, AC138517.2, AC138647.1,AC138696.1, AC138811.2, AC138894.1, AC138969.1, AC139530.2, AC139677.1,AC139677.2, AC140504.1, AC141272.1, AC142391.1, AC142525.4, AC145029.2,AC145212.1, AC145212.2, AC171558.1, AC171558.3, AC171558.5, AC171558.6,AC187653.1, AC207056.1, AC209232.1, AC209539.2, AC210544.1, AC213203.1,AC229888.1, AC229888.10, AC229888.2, AC229888.3, AC229888.4, AC229888.5,AC229888.6, AC229888.7, AC229888.8, AC229888.9, AC233282.1, AC233282.2,AC233723.1, AC233724.12, AC233724.16, AC233724.17, AC233724.18,AC233724.19, AC233724.20, AC233724.21, AC233724.6, AC233755.1,AC233755.2, AC233992.2, AC234301.1, AC234301.3, AC234635.1, AC234635.3,AC234635.4, AC234635.5, AC236040.1, AC239612.1, AC239618.1, AC239618.2,AC239618.3, AC239618.4, AC239618.5, AC239618.6, AC239618.7, AC239618.9,AC239799.1, AC240274.1, AC241401.1, AC241409.2, AC241410.1, AC241556.3,AC241556.4, AC241640.1, AC241640.2, AC241640.4, AC242528.1, AC242528.2,AC243547.3, AC243733.1, AC243734.1, AC243756.1, AC243790.1, AC243967.1,AC244196.1, AC244196.2, AC244196.3, AC244196.4, AC244196.5, AC244197.3,AC244216.4, AC244216.5, AC244226.1, AC244226.2, AC244472.1, AC244472.2,AC244472.3, AC244472.4, AC244472.5, AC244489.1, AC244489.2, AC244517.10,AC244517.6, AC245033.1, AC245034.2, AC245078.1, AC245088.2, AC245088.3,AC245369.1, AC245369.2, AC245369.3, AC245369.4, AC245369.6, AC245427.1,AC245427.3, AC245427.4, AC245427.5, AC245427.6, AC245427.7, AC245427.8,AC245427.9, AC245748.1, AC247036.3, AC247036.4, AC247036.5, AC247036.6,AC254560.1, AC254788.1, AC254788.2, AC254952.1, AC255093.3, AC255093.5,AC256236.1, AC256236.2, AC256236.3, AC256300.2, AC256309.2, AC270107.1,AC270107.10, AC270107.12, AC270107.2, AC270107.3, AC270107.4,AC270107.5, AC270107.7, AC270107.8, AC270107.9, AC270227.1, AC270306.4,AC275455.2, ACAA1, ACAA2, ACACA, ACACB, ACAD10, ACAD11, ACAD8, ACAD9,ACADL, ACADM, ACADS, ACADSB, ACADVL, ACAN, ACAP1, ACAP2, ACAP3, ACAT1,ACAT2, ACBD3, ACBD4, ACBD5, ACBD6, ACBD7, ACCS, ACCSL, ACD, ACE, ACE2,ACER1, ACER2, ACER3, ACHE, ACIN1, ACKR1, ACKR2, ACKR3, ACKR4, ACLY,ACMSD, ACO1, ACO2, ACOD1, ACOT1, ACOT11, ACOT12, ACOT13, ACOT2, ACOT4,ACOT6, ACOT7, ACOT8, ACOT9, ACOX1, ACOX2, ACOX3, ACOXL, ACP1, ACP2,ACP4, ACP5, ACP6, ACP7, ACPP, ACR, ACRBP, ACRV1, ACSBG1, ACSBG2, ACSF2,ACSF3, ACSL1, ACSL3, ACSL4, ACSL5, ACSL6, ACSM1, ACSM2A, ACSM2B, ACSM3,ACSM4, ACSM5, ACSM6, ACSS1, ACSS2, ACSS3, ACTA1, ACTA2, ACTB, ACTBL2,ACTC1, ACTG1, ACTG2, ACTL10, ACTL6A, ACTL6B, ACTL7A, ACTL7B, ACTL8,ACTL9, ACTN1, ACTN2, ACTN3, ACTN4, ACTR10, ACTR1A, ACTR1B, ACTR2, ACTR3,ACTR3B, ACTR3C, ACTR5, ACTR6, ACTR8, ACTRT1, ACTRT2, ACTRT3, ACVR1,ACVR1B, ACVR1C, ACVR2A, ACVR2B, ACVRL1, ACY1, ACY3, ACYP1, ACYP2,AD000671.1, AD000671.2, ADA, ADA2, ADAD1, ADAD2, ADAL, ADAM10, ADAM11,ADAM12, ADAM15, ADAM17, ADAM18, ADAM19, ADAM2, ADAM20, ADAM21, ADAM22,ADAM23, ADAM28, ADAM29, ADAM30, ADAM32, ADAM33, ADAM7, ADAM8, ADAM9,ADAMDEC1, ADAMTS1, ADAMTS10, ADAMTS12, ADAMTS13, ADAMTS14, ADAMTS15,ADAMTS16, ADAMTS17, ADAMTS18, ADAMTS19, ADAMTS2, ADAMTS20, ADAMTS3,ADAMTS4, ADAMTS5, ADAMTS6, ADAMTS7, ADAMTS8, ADAMTS9, ADAMTSL1,ADAMTSL2, ADAMTSL3, ADAMTSL4, ADAMTSL5, ADAP1, ADAP2, ADAR, ADARB1,ADARB2, ADAT1, ADAT2, ADAT3, ADCK1, ADCK2, ADCK5, ADCY1, ADCY10, ADCY2,ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, ADCYAP1, ADCYAP1R1,ADD1, ADD2, ADD3, ADGB, ADGRA1, ADGRA2, ADGRA3, ADGRB1, ADGRB2, ADGRB3,ADGRD1, ADGRD2, ADGRE1, ADGRE2, ADGRE3, ADGRE5, ADGRF1, ADGRF2, ADGRF3,ADGRF4, ADGRF5, ADGRG1, ADGRG2, ADGRG3, ADGRG4, ADGRG5, ADGRG6, ADGRG7,ADGRL1, ADGRL2, ADGRL3, ADGRL4, ADGRV1, ADH1A, ADH1B, ADH1C, ADH4, ADH5,ADH6, ADH7, ADHFE1, ADI1, ADIG, ADIPOQ, ADIPOR1, ADIPOR2, ADIRF, ADK,ADM, ADM2, ADM5, ADNP, ADNP2, ADO, ADORA1, ADORA2A, ADORA2B, ADORA3,ADPGK, ADPRH, ADPRHL1, ADPRHL2, ADPRM, ADRA1A, ADRA1B, ADRA1D, ADRA2A,ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3, ADRM1, ADSL, ADSS, ADSSL1, ADTRP,AEBP1, AEBP2, AEN, AES, AF130351.1, AF241726.2, AFAP1, AFAP1L1, AFAP1L2,AFDN, AFF1, AFF2, AFF3, AFF4, AFG1L, AFG3L2, AFM, AFMID, AFP, AFTPH,AGA, AGAP1, AGAP2, AGAP3, AGAP4, AGAP5, AGAP6, AGAP9, AGBL1, AGBL2,AGBL3, AGBL4, AGBL5, AGER, AGFG1, AGFG2, AGGF1, AGK, AGL, AGMAT, AGMO,AGO1, AGO2, AGO3, AGO4, AGPAT1, AGPAT2, AGPAT3, AGPAT4, AGPAT5, AGPS,AGR2, AGR3, AGRN, AGRP, AGT, AGTPBP1, AGTR1, AGTR2, AGTRAP, AGXT, AGXT2,AHCTF1, AHCY, AHCYL1, AHCYL2, AHDC1, AHI1, AHNAK, AHNAK2, AHR, AHRR,AHSA1, AHSA2, AHSG, AHSP, AICDA, AIDA, AIF1, AIF1L, AIFM1, AIFM2, AIFM3,AIG1, AIM2, AIMP1, AIMP2, AIP, AIPL1, AIRE, AJAP1, AJUBA, AK1, AK2, AK3,AK4, AK5, AK6, AK7, AK8, AK9, AKAIN1, AKAP1, AKAP10, AKAP11, AKAP12,AKAP13, AKAP14, AKAP17A, AKAP2, AKAP3, AKAP4, AKAP5, AKAP6, AKAP7,AKAP8, AKAP8L, AKAP9, AKIP1, AKIRIN1, AKIRIN2, AKNA, AKNAD1, AKR1A1,AKR1B1, AKR1B10, AKR1B15, AKR1C1, AKR1C2, AKR1C3, AKR1C4, AKR1D1,AKR1E2, AKR7A2, AKR7A3, AKR7L, AKT1, AKT1S1, AKT2, AKT3, AKTIP,AL020996.2, AL021154.3, AL021546.1, AL021997.3, AL022238.4, AL022318.4,AL024498.2, AL031708.1, AL032819.3, AL033529.1, AL035425.2, AL035460.1,AL049634.2, AL049650.1, AL049697.1, AL049779.1, AL049839.2, AL049844.1,AL049844.3, AL080251.1, AL096814.1, AL096870.1, AL109810.2, AL109811.4,AL109827.1, AL109936.3, AL109936.4, AL110118.2, AL110118.4, AL117258.1,AL117339.5, AL117348.2, AL121581.1, AL121594.3, AL121722.1, AL121753.1,AL121758.1, AL121845.2, AL121845.3, AL132671.2, AL132780.3, AL133352.1,AL133414.1, AL133414.2, AL136295.1, AL136295.3, AL136295.4, AL136295.5,AL136373.1, AL136531.2, AL138694.1, AL138752.2, AL138826.1, AL139011.2,AL139260.3, AL139300.1, AL139353.1, AL157392.5, AL159163.1, AL160275.1,AL160276.1, AL160396.2, AL161669.4, AL161911.1, AL162231.1, AL162231.3,AL163195.3, AL163636.2, AL353572.3, AL353588.1, AL354761.2, AL354822.1,AL355102.2, AL355315.1, AL355860.1, AL355916.3, AL355987.1, AL355987.3,AL356585.9, AL357673.1, AL358075.4, AL359736.1, AL359736.3, AL359922.1,AL360181.3, AL360181.5, AL365205.1, AL365214.3, AL365232.1, AL365273.2,AL391650.1, AL449266.1, AL451007.3, AL512428.1, AL512506.3, AL512785.2,AL513165.2, AL513523.10, AL513523.9, AL583836.1, AL589666.1, AL590132.1,AL590560.1, AL591806.3, AL592183.1, AL592490.1, AL593848.2, AL603832.3,AL645922.1, AL645941.2, AL662828.1, AL662852.6, AL662899.1, AL662899.2,AL662899.3, AL669918.1, AL672043.1, AL672142.1, AL691442.1, AL713999.1,AL772284.2, AL807752.6, AL807752.7, AL844853.2, AL845331.2, AL845464.1,AL928654.4, AL929554.1, AL929561.7, ALAD, ALAS1, ALAS2, ALB, ALCAM,ALDH16A1, ALDH18A1, ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1,ALDH1L2, ALDH2, ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, ALDH4A1, ALDH5A1,ALDH6A1, ALDH7A1, ALDH8A1, ALDH9A1, ALDOA, ALDOB, ALDOC, ALG1, ALG10,ALG10B, ALG11, ALG12, ALG13, ALG14, ALG1L, ALG1L2, ALG2, ALG3, ALG5,ALG6, ALG8, ALG9, ALK, ALKAL1, ALKAL2, ALKBH1, ALKBH2, ALKBH3, ALKBH4,ALKBH5, ALKBH6, ALKBH7, ALKBH8, ALLC, ALMS1, ALOX12, ALOX12B, ALOX15,ALOX15B, ALOX5, ALOX5AP, ALOXE3, ALPI, ALPK1, ALPK2, ALPK3, ALPL, ALPP,ALPPL2, ALS2, ALS2CL, ALS2CR12, ALX1, ALX3, ALX4, ALYREF, AMACR, AMBN,AMBP, AMBRA1, AMD1, AMDHD1, AMDHD2, AMELX, AMELY, AMER1, AMER2, AMER3,AMFR, AMH, AMHR2, AMIGO1, AMIGO2, AMIGO3, AMMECR1, AMMECR1L, AMN, AMN1,AMOT, AMOTL1, AMOTL2, AMPD1, AMPD2, AMPD3, AMPH, AMT, AMTN, AMY1A,AMY1B, AMY1C, AMY2A, AMY2B, AMZ1, AMZ2, ANAPC1, ANAPC10, ANAPC11,ANAPC13, ANAPC15, ANAPC16, ANAPC2, ANAPC4, ANAPC5, ANAPC7, ANG, ANGEL1,ANGEL2, ANGPT1, ANGPT2, ANGPT4, ANGPTL1, ANGPTL2, ANGPTL3, ANGPTL4,ANGPTL5, ANGPTL6, ANGPTL7, ANGPTL8, ANHX, ANK1, ANK2, ANK3, ANKAR,ANKDD1A, ANKDD1B, ANKEF1, ANKFN1, ANKFY1, ANKH, ANKHD1, ANKHD1-EIF4EBP3,ANKIB1, ANKK1, ANKLE1, ANKLE2, ANKMY1, ANKMY2, ANKRA2, ANKRD1, ANKRD10,ANKRD11, ANKRD12, ANKRD13A, ANKRD13B, ANKRD13C, ANKRD13D, ANKRD16,ANKRD17, ANKRD18A, ANKRD18B, ANKRD2, ANKRD20A1, ANKRD20A2, ANKRD20A3,ANKRD20A4, ANKRD20A8P, ANKRD22, ANKRD23, ANKRD24, ANKRD26, ANKRD27,ANKRD28, ANKRD29, ANKRD30A, ANKRD30B, ANKRD30BL, ANKRD31, ANKRD33,ANKRD33B, ANKRD34A, ANKRD34B, ANKRD34C, ANKRD35, ANKRD36, ANKRD36B,ANKRD36C, ANKRD37, ANKRD39, ANKRD40, ANKRD42, ANKRD44, ANKRD45, ANKRD46,ANKRD49, ANKRD50, ANKRD52, ANKRD53, ANKRD54, ANKRD55, ANKRD6, ANKRD60,ANKRD61, ANKRD62, ANKRD63, ANKRD65, ANKRD66, ANKRD7, ANKRD9, ANKS1A,ANKS1B, ANKS3, ANKS4B, ANKS6, ANKUB1, ANKZF1, ANLN, ANO1, ANO10, ANO2,ANO3, ANO4, ANO5, ANO6, ANO7, ANO8, ANO9, ANOS1, ANP32A, ANP32B, ANP32D,ANP32E, ANPEP, ANTXR1, ANTXR2, ANTXRL, ANXA1, ANXA10, ANXA11, ANXA13,ANXA2, ANXA2R, ANXA3, ANXA4, ANXA5, ANXA6, ANXA7, ANXA8, ANXA8L1, ANXA9,AOAH, AOC1, AOC2, AOC3, AOX1, AP000275.2, AP000295.1, AP000311.1,AP000322.1, AP000349.1, AP000350.12, AP000350.4, AP000351.3, AP000351.7,AP000721.1, AP000781.2, AP001160.5, AP001273.2, AP001458.2, AP001781.3,AP001931.1, AP002360.1, AP002373.1, AP002495.1, AP002512.3, AP002512.4,AP002748.4, AP002990.1, AP003071.5, AP003108.2, AP003419.2, AP004243.1,AP006285.3, AP1AR, AP1B1, AP1G1, AP1G2, AP1M1, AP1M2, AP1S1, AP1S2,AP1S3, AP2A1, AP2A2, AP2B1, AP2M1, AP2S1, AP3B1, AP3B2, AP3D1, AP3M1,AP3M2, AP3S1, AP3S2, AP4B1, AP4E1, AP4M1, AP4S1, AP5B1, AP5M1, AP5S1,AP5Z1, APAF1, APBA1, APBA2, APBA3, APBB1, APBB1IP, APBB2, APBB3, APC,APC2, APCDD1, APCDD1L, APCS, APEH, APELA, APEX1, APEX2, APH1A, APH1B,API5, APIP, APLF, APLN, APLNR, APLP1, APLP2, APMAP, APOA1, APOA2, APOA4,APOA5, APOB, APOBEC1, APOBEC2, APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D,APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4, APOBR, APOC1, APOC2, APOC3,APOC4, APOC4-APOC2, APOD, APOE, APOF, APOH, APOL1, APOL2, APOL3, APOL4,APOL5, APOL6, APOLD1, APOM, APOO, APOOL, APOPT1, APP, APPBP2, APPL1,APPL2, APRT, APTX, AQP1, AQP10, AQP11, AQP12A, AQP12B, AQP2, AQP3, AQP4,AQP5, AQP6, AQP7, AQP8, AQP9, AQR, AR, ARAF, ARAP1, ARAP2, ARAP3, ARC,ARCN1, AREG, AREL1, ARF1, ARF3, ARF4, ARF5, ARF6, ARFGAP1, ARFGAP2,ARFGAP3, ARFGEF1, ARFGEF2, ARFGEF3, ARFIP1, ARFIP2, ARFRP1, ARG1, ARG2,ARGFX, ARGLU1, ARHGAP1, ARHGAP10, ARHGAP11A, ARHGAP11B, ARHGAP12,ARHGAP15, ARHGAP17, ARHGAP18, ARHGAP19, ARHGAP19-SLIT1, ARHGAP20,ARHGAP21, ARHGAP22, ARHGAP23, ARHGAP24, ARHGAP25, ARHGAP26, ARHGAP27,ARHGAP28, ARHGAP29, ARHGAP30, ARHGAP31, ARHGAP32, ARHGAP33, ARHGAP35,ARHGAP36, ARHGAP39, ARHGAP4, ARHGAP40, ARHGAP42, ARHGAP44, ARHGAP45,ARHGAP5, ARHGAP6, ARHGAP8, ARHGAP9, ARHGDIA, ARHGDIB, ARHGDIG, ARHGEF1,ARHGEF10, ARHGEF10L, ARHGEF11, ARHGEF12, ARHGEF15, ARHGEF16, ARHGEF17,ARHGEF18, ARHGEF19, ARHGEF2, ARHGEF25, ARHGEF26, ARHGEF28, ARHGEF3,ARHGEF33, ARHGEF35, ARHGEF37, ARHGEF38, ARHGEF39, ARHGEF4, ARHGEF40,ARHGEF5, ARHGEF6, ARHGEF7, ARHGEF9, ARID1A, ARIDIB, ARID2, ARID3A,ARID3B, ARID3C, ARID4A, ARID4B, ARID5A, ARID5B, ARIH1, ARIH2, ARIH2OS,ARL1, ARL10, ARL11, ARL13A, ARL13B, ARL14, ARL14EP, ARL14EPL, ARL15,ARL16, ARL17A, ARL17B, ARL2, ARL2BP, ARL2-SNX15, ARL3, ARL4A, ARL4C,ARL4D, ARL5A, ARL5B, ARL5C, ARL6, ARL6IP1, ARL6IP4, ARL6IP5, ARL6IP6,ARL8A, ARL8B, ARL9, ARMC1, ARMC10, ARMC12, ARMC2, ARMC3, ARMC4, ARMC5,ARMC6, ARMC7, ARMC8, ARMC9, ARMCX1, ARMCX2, ARMCX3, ARMCX4, ARMCX5,ARMCX6, ARMS2, ARMT1, ARNT, ARNT2, ARNTL, ARNTL2, ARPC1A, ARPCIB, ARPC2,ARPC3, ARPC4, ARPC4-TTLL3, ARPC5, ARPC5L, ARPIN, ARPP19, ARPP21, ARR3,ARRB1, ARRB2, ARRDC1, ARRDC2, ARRDC3, ARRDC4, ARRDC5, ARSA, ARSB, ARSD,ARSE, ARSF, ARSG, ARSH, ARSI, ARSJ, ARSK, ART1, ART3, ART4, ART5, ARTN,ARV1, ARVCF, ARX, AS3MT, ASAH1, ASAH2, ASAH2B, ASAP1, ASAP2, ASAP3,ASB1, ASB10, ASB11, ASB12, ASB13, ASB14, ASB15, ASB16, ASB17, ASB18,ASB2, ASB3, ASB4, ASB5, ASB6, ASB7, ASB8, ASB9, ASCC1, ASCC2, ASCC3,ASCL1, ASCL2, ASCL3, ASCL4, ASCL5, ASF1A, ASF1B, ASGR1, ASGR2, ASH1L,ASH2L, ASIC1, ASIC2, ASIC3, ASIC4, ASIC5, ASIP, ASL, ASMT, ASMTL, ASNA1,ASNS, ASNSD1, ASPA, ASPDH, ASPG, ASPH, ASPHD1, ASPHD2, ASPM, ASPN,ASPRV1, ASPSCR1, ASRGL1, ASS1, ASTE1, ASTL, ASTN1, ASTN2, ASXL1, ASXL2,ASXL3, ASZ1, ATAD1, ATAD2, ATAD2B, ATAD3A, ATAD3B, ATAD3C, ATAD5, ATAT1,ATCAY, ATE1, ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, ATF6B, ATF7, ATF7IP,ATF7IP2, ATG10, ATG101, ATG12, ATG13, ATG14, ATG16L1, ATG16L2, ATG2A,ATG2B, ATG3, ATG4A, ATG4B, ATG4C, ATG4D, ATG5, ATG7, ATG9A, ATG9B, ATIC,ATL1, ATL2, ATL3, ATM, ATMIN, ATN1, ATOH1, ATOH7, ATOH8, ATOX1, ATP10A,ATP10B, ATP10D, ATP11A, ATP11B, ATP11C, ATP12A, ATP13A1, ATP13A2,ATP13A3, ATP13A4, ATP13A5, ATP1A1, ATP1A2, ATP1A3, ATP1A4, ATP1B1,ATP1B2, ATP1B3, ATP1B4, ATP23, ATP2A1, ATP2A2, ATP2A3, ATP2B1, ATP2B2,ATP2B3, ATP2B4, ATP2C1, ATP2C2, ATP4A, ATP4B, ATP5A1, ATP5B, ATP5C1,ATP5D, ATP5E, ATP5EP2, ATP5F1, ATP5G1, ATP5G2, ATP5G3, ATP5H, ATP5I,ATP5J, ATP5J2, ATP5J2-PTCD1, ATP5L, ATP5L2, ATP50, ATP5S, ATP6AP1,ATP6AP1L, ATP6AP2, ATP6VOA1, ATP6VOA2, ATP6VOA4, ATP6VOB, ATP6VOC,ATP6VOD1, ATP6VOD2, ATP6VOE1, ATP6VOE2, ATP6V1A, ATP6V1B1, ATP6V1B2,ATP6V1C1, ATP6V1C2, ATP6V1D, ATP6V1E1, ATP6V1E2, ATP6V1F, ATP6V1G1,ATP6V1G2, ATP6V1G2-DDX39B, ATP6V1G3, ATP6V1H, ATP7A, ATP7B, ATP8A1,ATP8A2, ATP8B1, ATP8B2, ATP8B3, ATP8B4, ATP9A, ATP9B, ATPAF1, ATPAF2,ATPIF1, ATR, ATRAID, ATRIP, ATRN, ATRNL1, ATRX, ATXN1, ATXN10, ATXN1L,ATXN2, ATXN2L, ATXN3, ATXN3L, ATXN7, ATXN7L1, ATXN7L2, ATXN7L3,ATXN7L3B, AUH, AUNIP, AUP1, AURKA, AURKAIP1, AURKB, AURKC, AUTS2, AVEN,AVIL, AVL9, AVP, AVPI1, AVPR1A, AVPR1B, AVPR2, AWAT1, AWAT2, AXDND1,AXIN1, AXIN2, AXL, AZGP1, AZI2, AZIN1, AZIN2, AZU1, B2M, B3GALNT1,B3GALNT2, B3GALT1, B3GALT2, B3GALT4, B3GALT5, B3GALT6, B3GAT1, B3GAT2,B3GAT3, B3GLCT, B3GNT2, B3GNT3, B3GNT4, B3GNT5, B3GNT6, B3GNT7, B3GNT8,B3GNT9, B3GNTL1, B4GALNT1, B4GALNT2, B4GALNT3, B4GALNT4, B4GALT1,B4GALT2, B4GALT3, B4GALT4, B4GALT5, B4GALT6, B4GALT7, B4GAT1, B9D1,B9D2, BAALC, BAAT, BABAM1, BABAM2, BACE1, BACE2, BACH1, BACH2, BAD,BAG1, BAG2, BAG3, BAG4, BAG5, BAG6, BAGE3, BAHCC1, BAHD1, BAIAP2,BAIAP2L1, BAIAP2L2, BAIAP3, BAK1, BAMBI, BANF1, BANF2, BANK1, BANP,BAP1, BARD1, BARHL1, BARHL2, BARX1, BARX2, BASP1, BATF, BATF2, BATF3,BAX, BAZ1A, BAZ1B, BAZ2A, BAZ2B, BBC3, BBIP1, BBOF1, BBOX1, BBS1, BBS10,BBS12, BBS2, BBS4, BBS5, BBS7, BBS9, BBX, BCAM, BCAN, BCAP29, BCAP31,BCAR1, BCAR3, BCAS1, BCAS2, BCAS3, BCAS4, BCAT1, BCAT2, BCCIP, BCDIN3D,BCHE, BCKDHA, BCKDHB, BCKDK, BCL10, BCL11A, BCL11B, BCL2, BCL2A1,BCL2L1, BCL2L10, BCL2L11, BCL2L12, BCL2L13, BCL2L14, BCL2L15, BCL2L2,BCL2L2-PABPN1, BCL3, BCL6, BCL6B, BCL7A, BCL7B, BCL7C, BCL9, BCL9L,BCLAF1, BCLAF3, BCO1, BCO2, BCOR, BCORL1, BCR, BCS1L, BDH1, BDH2,BDKRB1, BDKRB2, BDNF, BDP1, BEAN1, BECN1, BECN2, BEGAIN, BEND2, BEND3,BEND4, BEND5, BEND6, BEND7, BEST1, BEST2, BEST3, BEST4, BET1, BET1L,BEX1, BEX2, BEX3, BEX4, BEX5, BFAR, BFSP1, BFSP2, BGLAP, BGN, BHLHA15,BHLHA9, BHLHB9, BHLHE22, BHLHE23, BHLHE40, BHLHE41, BHMG1, BHMT, BHMT2,BICC1, BICD1, BICD2, BICDL1, BICDL2, BICRA, BICRAL, BID, BIK, BIN1,BIN2, BIN3, BIRC2, BIRC3, BIRC5, BIRC6, BIRC7, BIRC8, BIVM, BIVM-ERCC5,BLACE, BLCAP, BLID, BLK, BLM, BLMH, BLNK, BLOC1S1, BLOC1S2, BLOC1S3,BLOC1S4, BLOC1S5, BLOC1S5-TXNDC5, BLOC1S6, BLVRA, BLVRB, BLZF1, BMF,BMI1, BMP1, BMP10, BMP15, BMP2, BMP2K, BMP3, BMP4, BMP5, BMP6, BMP7,BMP8A, BMP8B, BMPER, BMPR1A, BMPR1B, BMPR2, BMS1, BMT2, BMX, BNC1, BNC2,BNIP1, BNIP2, BNIP3, BNIP3L, BNIPL, BOC, BOD1, BOD1L1, BOD1L2, BOK,BOLA1, BOLA2, BOLA2B, BOLA2-SMG1P6, BOLA3, BOLL, BOP1, BORA, BORCS5,BORCS6, BORCS7, BORCS7-ASMT, BORCS8, BORCS8-MEF2B, BPGM, BPHL, BPI,BPIFA1, BPIFA2, BPIFA3, BPIFB1, BPIFB2, BPIFB3, BPIFB4, BPIFB6, BPIFC,BPNT1, BPTF, BPY2, BPY2B, BPY2C, BRAF, BRAP, BRAT1, BRCA1, BRCA2, BRCC3,BRD1, BRD2, BRD3, BRD4, BRD7, BRD8, BRD9, BRDT, BRF1, BRF2, BRI3,BRI3BP, BRICD5, BRINP1, BRINP2, BRINP3, BRIP1, BRIX1, BRK1, BRMS1,BRMS1L, BROX, BRPF1, BRPF3, BRS3, BRSK1, BRSK2, BRWD1, BRWD3, BSCL2,BSDC1, BSG, BSN, BSND, BSPH1, BSPRY, BST1, BST2, BSX, BTAF1, BTBD1,BTBD10, BTBD11, BTBD16, BTBD17, BTBD18, BTBD19, BTBD2, BTBD3, BTBD6,BTBD7, BTBD8, BTBD9, BTC, BTD, BTF3, BTF3L4, BTG1, BTG2, BTG3, BTG4,BTK, BTLA, BTN1A1, BTN2A1, BTN2A2, BTN3A1, BTN3A2, BTN3A3, BTNL2, BTNL3,BTNL8, BTNL9, BTRC, BUB1, BUB1B, BUB1B-PAK6, BUB3, BUD13, BUD23, BUD31,BVES, BX004987.1, BX072566.1, BX088645.1, BX248244.1, BX248413.4,BX248415.1, BX248516.1, BX276092.9, BYSL, BZW1, BZW2, C10orf10,C10orf105, C10orf107, C10orf113, C10orf120, C10orf126, C10orf128,C10orf142, C10orf35, C10orf53, C10orf55, C10orf62, C10orf67, C10orf71,C10orf76, C10orf82, C10orf88, C10orf90, C10orf95, C10orf99, C11orf1,C11orf16, C11orf21, C11orf24, C11orf40, C11orf42, C11orf45, C11orf49,C11orf52, C11orf53, C11orf54, C11orf57, C11orf58, C11orf63, C11orf65,C11orf68, C11orf70, C11orf71, C11orf74, C11orf80, C11orf84, C11orf86,C11orf87, C11orf88, C11orf91, C11orf94, C11orf95, C11orf96, C11orf97,C11orf98, C12orf10, C12orf29, C12orf4, C12orf40, C12orf42, C12orf43,C12orf45, C12orf49, C12orf50, C12orf54, C12orf56, C12orf57, C12orf60,C12orf65, C12orf66, C12orf71, C12orf73, C12orf74, C12orf75, C12orf76,C13orf42, C14orf105, C14orf119, C14orf132, C14orf159, C14orf166,C14orf177, C14orf178, C14orf180, C14orf2, C14orf28, C14orf37, C14orf39,C14orf79, C14orf80, C14orf93, C15orf38-AP3S2, C15orf39, C15orf40,C15orf41, C15orf48, C15orf52, C15orf53, C15orf59, C15orf61, C15orf62,C15orf65, C16orf45, C16orf46, C16orf52, C16orf54, C16orf58, C16orf59,C16orf62, C16orf70, C16orf71, C16orf72, C16orf74, C16orf78, C16orf82,C16orf86, C16orf87, C16orf89, C16orf90, C16orf91, C16orf92, C16orf95,C16orf96, C17orf100, C17orf105, C17orf107, C17orf113, C17orf47,C17orf49, C17orf50, C17orf51, C17orf53, C17orf58, C17orf62, C17orf64,C17orf67, C17orf74, C17orf75, C17orf78, C17orf80, C17orf97, C17orf98,C17orf99, C18orf21, C18orf25, C18orf32, C18orf54, C18orf63, C18orf8,C19orf12, C19orf18, C19orf24, C19orf25, C19orf33, C19orf35, C19orf38,C19orf44, C19orf47, C19orf48, C19orf53, C19orf54, C19orf57, C19orf60,C19orf66, C19orf67, C19orf68, C19orf70, C19orf71, C19orf73, C19orf81,C19orf84, C1D, C1GALT1, C1GALT1C1, C1GALT1C1L, C1orf100, C1orf105,C1orf109, C1orf112, C1orf115, C1orf116, C1orf122, C1orf123, C1orf127,C1orf131, C1orf141, C1orf146, C1orf158, C1orf159, C1orf162, C1orf167,C1orf174, C1orf185, C1orf186, C1orf189, C1orf194, C1orf198, C1orf21,C1orf210, C1orf216, C1orf226, C1orf228, C1orf232, C1orf27, C1orf35,C1orf43, C1orf50, C1orf52, C1orf53, C1orf54, C1orf56, C1orf61, C1orf64,C1orf68, C1orf74, C1orf87, C1orf94, C1QA, C1QB, C1QBP, C1QC, C1QL1,C1QL2, C1QL3, C1QL4, C1QTNF1, C1QTNF12, C1QTNF2, C1QTNF3, C1QTNF3-AMACR,C1QTNF4, C1QTNF5, C1QTNF6, C1QTNF7, C1QTNF8, C1QTNF9, C1QTNF9B, C1R,C1RL, C1S, C2, C20orf141, C20orf144, C20orf173, C20orf194, C20orf196,C20orf202, C20orf204, C20orf24, C20orf27, C20orf85, C20orf96, C21orf140,C21orf2, C21orf33, C21orf58, C21orf59, C21orf62, C21orf91, C22orf15,C22orf23, C22orf31, C22orf39, C22orf42, C22orf46, C2CD2, C2CD2L, C2CD3,C2CD4A, C2CD4B, C2CD4C, C2CD4D, C2CD5, C2CD6, C2orf15, C2orf16, C2orf40,C2orf42, C2orf49, C2orf50, C2orf54, C2orf66, C2orf68, C2orf69, C2orf70,C2orf71, C2orf72, C2orf73, C2orf74, C2orf76, C2orf78, C2orf80, C2orf81,C2orf82, C2orf83, C2orf88, C2orf91, C3, C3AR1, C3orf14, C3orf18,C3orf20, C3orf22, C3orf30, C3orf33, C3orf35, C3orf36, C3orf38, C3orf49,C3orf52, C3orf56, C3orf58, C3orf62, C3orf67, C3orf70, C3orf80, C3orf84,C3orf85, C4A, C4B, C4B_2, C4BPA, C4BPB, C4orf17, C4orf19, C4orf22,C4orf26, C4orf3, C4orf32, C4orf33, C4orf36, C4orf45, C4orf46, C4orf47,C4orf48, C4orf50, C4orf51, C5, C5AR1, C5AR2, C5orf15, C5orf22, C5orf24,C5orf30, C5orf34, C5orf38, C5orf42, C5orf46, C5orf47, C5orf49, C5orf51,C5orf52, C5orf56, C5orf58, C5orf60, C5orf63, C5orf67, C6, C6orf10,C6orf106, C6orf118, C6orf120, C6orf132, C6orf136, C6orf141, C6orf15,C6orf163, C6orf201, C6orf203, C6orf222, C6orf223, C6orf226, C6orf229,C6orf47, C6orf48, C6orf52, C6orf58, C6orf62, C6orf89, C7, C7orf25,C7orf26, C7orf31, C7orf33, C7orf34, C7orf43, C7orf49, C7orf50,C7orf55-LUC7L2, C7orf57, C7orf61, C7orf72, C7orf73, C7orf77, C8A, C8B,C8G, C8orf22, C8orf33, C8orf34, C8orf37, C8orf4, C8orf44, C8orf44-SGK3,C8orf46, C8orf48, C8orf58, C8orf59, C8orf74, C8orf76, C8orf82, C8orf86,C8orf88, C8orf89, C9, C9orf116, C9orf129, C9orf131, C9orf135, C9orf152,C9orf153, C9orf16, C9orf172, C9orf24, C9orf3, C9orf40, C9orf43, C9orf47,C9orf50, C9orf57, C9orf64, C9orf66, C9orf72, C9orf78, C9orf84, C9orf85,C9orf92, CA1, CA10, CA11, CA12, CA13, CA14, CA2, CA3, CA4, CA5A, CA5B,CA6, CA7, CA8, CA9, CAAP1, CAB39, CAB39L, CABIN1, CABLES1, CABLES2,CABP1, CABP2, CABP4, CABP5, CABP7, CABS1, CABYR, CACFD1, CACHD1,CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H,CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1,CACNB2, CACNB3, CACNB4, CACNG1, CACNG2, CACNG3, CACNG4, CACNG5, CACNG6,CACNG7, CACNG8, CACTIN, CACUL1, CACYBP, CAD, CADM1, CADM2, CADM3, CADM4,CADPS, CADPS2, CAGE1, CALB1, CALB2, CALCA, CALCB, CALCOCO1, CALCOCO2,CALCR, CALCRL, CALD1, CALHM1, CALHM2, CALHM3, CALM1, CALM2, CALM3,CALML3, CALML4, CALML5, CALML6, CALN1, CALR, CALR3, CALU, CALY, CAMK1,CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CAMK2N1, CAMK2N2, CAMK4,CAMKK1, CAMKK2, CAMKMT, CAMKV, CAMLG, CAMP, CAMSAP1, CAMSAP2, CAMSAP3,CAMTA1, CAMTA2, CAND1, CAND2, CANT1, CANX, CAP1, CAP2, CAPG, CAPN1,CAPN10, CAPN11, CAPN12, CAPN13, CAPN14, CAPN15, CAPN2, CAPN3, CAPN5,CAPN6, CAPN7, CAPN8, CAPN9, CAPNS1, CAPNS2, CAPRIN1, CAPRIN2, CAPS,CAPS2, CAPSL, CAPZA1, CAPZA2, CAPZA3, CAPZB, CARD10, CARD11, CARD14,CARD16, CARD17, CARD18, CARD19, CARD6, CARD8, CARD9, CARF, CARHSP1,CARM1, CARMIL1, CARMIL2, CARMIL3, CARNMT1, CARNS1, CARS, CARS2, CARTPT,CASC1, CASC10, CASC3, CASC4, CASD1, CASK, CASKIN1, CASKIN2, CASP1,CASP10, CASP12, CASP14, CASP2, CASP3, CASP4, CASP5, CASP6, CASP7, CASP8,CASP8AP2, CASP9, CASQ1, CASQ2, CASR, CASS4, CAST, CASTOR1, CASTOR2,CASZ1, CAT, CATIP, CATSPER1, CATSPER2, CATSPER3, CATSPER4, CATSPERB,CATSPERD, CATSPERE, CATSPERG, CATSPERZ, CAV1, CAV2, CAV3, CAVIN1,CAVIN2, CAVIN3, CAVIN4, CBARP, CBFA2T2, CBFA2T3, CBFB, CBL, CBLB, CBLC,CBLL1, CBLN1, CBLN2, CBLN3, CBLN4, CBR1, CBR3, CBR4, CBS, CBSL, CBWD1,CBWD2, CBWD3, CBWD5, CBWD6, CBX1, CBX2, CBX3, CBX4, CBX5, CBX6, CBX7,CBX8, CBY1, CBY3, CC2D1A, CC2D1B, CC2D2A, CC2D2B, CCAR1, CCAR2, CCBE1,CCDC102A, CCDC102B, CCDC103, CCDC105, CCDC106, CCDC107, CCDC110,CCDC112, CCDC113, CCDC114, CCDC115, CCDC116, CCDC117, CCDC12, CCDC120,CCDC121, CCDC122, CCDC124, CCDC125, CCDC126, CCDC127, CCDC129, CCDC13,CCDC130, CCDC134, CCDC136, CCDC137, CCDC138, CCDC14, CCDC140, CCDC141,CCDC142, CCDC144A, CCDC144NL, CCDC146, CCDC148, CCDC149, CCDC15,CCDC150, CCDC151, CCDC152, CCDC153, CCDC154, CCDC155, CCDC157, CCDC158,CCDC159, CCDC160, CCDC163, CCDC166, CCDC167, CCDC168, CCDC169,CCDC169-SOHLH2, CCDC17, CCDC170, CCDC171, CCDC172, CCDC173, CCDC174,CCDC175, CCDC177, CCDC178, CCDC179, CCDC18, CCDC180, CCDC181, CCDC182,CCDC183, CCDC184, CCDC185, CCDC186, CCDC187, CCDC188, CCDC189, CCDC190,CCDC191, CCDC192, CCDC194, CCDC195, CCDC196, CCDC197, CCDC22, CCDC24,CCDC25, CCDC27, CCDC28A, CCDC28B, CCDC3, CCDC30, CCDC32, CCDC33, CCDC34,CCDC36, CCDC38, CCDC39, CCDC40, CCDC42, CCDC43, CCDC47, CCDC50, CCDC51,CCDC54, CCDC57, CCDC58, CCDC59, CCDC6, CCDC60, CCDC61, CCDC62, CCDC63,CCDC65, CCDC66, CCDC68, CCDC69, CCDC7, CCDC70, CCDC71, CCDC71L, CCDC73,CCDC74A, CCDC74B, CCDC77, CCDC78, CCDC8, CCDC80, CCDC81, CCDC82, CCDC83,CCDC84, CCDC85A, CCDC85B, CCDC85C, CCDC86, CCDC87, CCDC88A, CCDC88B,CCDC88C, CCDC89, CCDC9, CCDC90B, CCDC91, CCDC92, CCDC93, CCDC94, CCDC96,CCDC97, CCER1, CCER2, CCHCR1, CCIN, CCK, CCKAR, CCKBR, CCL1, CCL11,CCL13, CCL14, CCL15, CCL15-CCL14, CCL16, CCL17, CCL18, CCL19, CCL2,CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CCL3,CCL3L1, CCL3L3, CCL4, CCL4L2, CCL5, CCL7, CCL8, CCM2, CCM2L, CCNA1,CCNA2, CCNB1, CCNB1IP1, CCNB2, CCNB3, CCNC, CCND1, CCND2, CCND3,CCNDBP1, CCNE1, CCNE2, CCNF, CCNG1, CCNG2, CCNH, CCNI, CCNI2, CCNJ,CCNJL, CCNK, CCNL1, CCNL2, CCNO, CCNT1, CCNT2, CCNY, CCNYL1, CCP110,CCPG1, CCR1, CCR10, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9,CCRL2, CCS, CCSAP, CCSER1, CCSER2, CCT2, CCT3, CCT4, CCT5, CCT6A, CCT6B,CCT7, CCT8, CCT8L2, CCZ1, CCZ1B, CD101, CD109, CD14, CD151, CD160,CD163, CD163L1, CD164, CD164L2, CD177, CD180, CD19, CD1A, CD1B, CD1C,CD1D, CD1E, CD2, CD200, CD200R1, CD200R1L, CD207, CD209, CD22, CD226,CD24, CD244, CD247, CD248, CD27, CD274, CD276, CD28, CD2AP, CD2BP2,CD300A, CD300C, CD300E, CD300LB, CD300LD, CD300LF, CD300LG, CD302,CD320, CD33, CD34, CD36, CD37, CD38, CD3D, CD3E, CD3EAP, CD3G, CD4,CD40, CD40LG, CD44, CD46, CD47, CD48, CD5, CD52, CD53, CD55, CD58, CD59,CD5L, CD6, CD63, CD68, CD69, CD7, CD70, CD72, CD74, CD79A, CD79B, CD80,CD81, CD82, CD83, CD84, CD86, CD8A, CD8B, CD9, CD93, CD96, CD99, CD99L2,CDA, CDADC1, CDAN1, CDC123, CDC14A, CDC14B, CDC16, CDC20, CDC20B, CDC23,CDC25A, CDC25B, CDC25C, CDC26, CDC27, CDC34, CDC37, CDC37L1, CDC40,CDC42, CDC42BPA, CDC42BPB, CDC42BPG, CDC42EP1, CDC42EP2, CDC42EP3,CDC42EP4, CDC42EP5, CDC42SE1, CDC42SE2, CDC45, CDC5L, CDC6, CDC7, CDC73,CDCA2, CDCA3, CDCA4, CDCA5, CDCA7, CDCA7L, CDCA8, CDCP1, CDCP2, CDH1,CDH10, CDH11, CDH12, CDH13, CDH15, CDH16, CDH17, CDH18, CDH19, CDH2,CDH20, CDH22, CDH23, CDH24, CDH26, CDH3, CDH4, CDH5, CDH6, CDH7, CDH8,CDH9, CDHR1, CDHR2, CDHR3, CDHR4, CDHR5, CDIP1, CDIPT, CDK1, CDK10,CDK11A, CDK11B, CDK12, CDK13, CDK14, CDK15, CDK16, CDK17, CDK18, CDK19,CDK2, CDK20, CDK2AP1, CDK2AP2, CDK3, CDK4, CDK5, CDK5R1, CDK5R2,CDK5RAP1, CDK5RAP2, CDK5RAP3, CDK6, CDK7, CDK8, CDK9, CDKAL1, CDKL1,CDKL2, CDKL3, CDKL4, CDKL5, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2AIP,CDKN2AIPNL, CDKN2B, CDKN2C, CDKN2D, CDKN3, CDNF, CDO1, CDON, CDPF1,CDR1, CDR2, CDR2L, CDRT1, CDRT15, CDRT15L2, CDRT4, CDS1, CDS2, CDSN,CDT1, CDV3, CDX1, CDX2, CDX4, CDY1, CDY1B, CDY2A, CDY2B, CDYL, CDYL2,CEACAM1, CEACAM16, CEACAM19, CEACAM20, CEACAM21, CEACAM3, CEACAM4,CEACAM5, CEACAM6, CEACAM7, CEACAM8, CEBPA, CEBPB, CEBPD, CEBPE, CEBPG,CEBPZ, CEBPZOS, CECR2, CEL, CELA1, CELA2A, CELA2B, CELA3A, CELA3B,CELF1, CELF2, CELF3, CELF4, CELF5, CELF6, CELSR1, CELSR2, CELSR3, CEMIP,CEMP1, CEND1, CENPA, CENPB, CENPBD1, CENPC, CENPE, CENPF, CENPH, CENPI,CENPJ, CENPK, CENPL, CENPM, CENPN, CENPO, CENPP, CENPQ, CENPS,CENPS-CORT, CENPT, CENPU, CENPV, CENPVL1, CENPVL2, CENPVL3, CENPW,CENPX, CEP104, CEP112, CEP120, CEP126, CEP128, CEP131, CEP135, CEP152,CEP162, CEP164, CEP170, CEP170B, CEP19, CEP192, CEP250, CEP290, CEP295,CEP295NL, CEP350, CEP41, CEP44, CEP55, CEP57, CEP57L1, CEP63, CEP68,CEP70, CEP72, CEP76, CEP78, CEP83, CEP85, CEP85L, CEP89, CEP95, CEP97,CEPT1, CER1, CERCAM, CERK, CERKL, CERS1, CERS2, CERS3, CERS4, CERS5,CERS6, CES1, CES2, CES3, CES4A, CESSA, CETN1, CETN2, CETN3, CETP,CFAP100, CFAP126, CFAP157, CFAP161, CFAP20, CFAP206, CFAP221, CFAP36,CFAP43, CFAP44, CFAP45, CFAP46, CFAP47, CFAP52, CFAP53, CFAP54, CFAP57,CFAP58, CFAP61, CFAP65, CFAP69, CFAP70, CFAP73, CFAP74, CFAP77, CFAP97,CFAP99, CFB, CFC1, CFC1B, CFD, CFDP1, CFH, CFHR1, CFHR2, CFHR3, CFHR4,CFHR5, CFI, CFL1, CFL2, CFLAR, CFP, CFTR, CGA, CGB1, CGB2, CGB3, CGB5,CGB7, CGB8, CGGBP1, CGN, CGNL1, CGREF1, CGRRF1, CH25H, CHAC1, CHAC2,CHAD, CHADL, CHAF1A, CHAF1B, CHAMP1, CHAT, CHCHD1, CHCHD10, CHCHD2,CHCHD3, CHCHD4, CHCHD5, CHCHD6, CHCHD7, CHD1, CHD1L, CHD2, CHD3, CHD4,CHD5, CHD6, CHD7, CHD8, CHD9, CHDH, CHEK1, CHEK2, CHERP, CHFR, CHGA,CHGB, CHI3L1, CHI3L2, CHIA, CHIC1, CHIC2, CHID1, CHIT1, CHKA, CHKB,CHKB-CPT1B, CHL1, CHM, CHML, CHMP1A, CHMP1B, CHMP2A, CHMP2B, CHMP3,CHMP4A, CHMP4B, CHMP4C, CHMP5, CHMP6, CHMP7, CHN1, CHN2, CHODL, CHORDC1,CHP1, CHP2, CHPF, CHPF2, CHPT1, CHRAC1, CHRD, CHRDL1, CHRDL2, CHRFAM7A,CHRM1, CHRM2, CHRM3, CHRM4, CHRM5, CHRNA1, CHRNA10, CHRNA2, CHRNA3,CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNB1, CHRNB2, CHRNB3, CHRNB4,CHRND, CHRNE, CHRNG, CHST1, CHST10, CHST11, CHST12, CHST13, CHST14,CHST15, CHST2, CHST3, CHST4, CHST5, CHST6, CHST7, CHST8, CHST9, CHSY1,CHSY3, CHTF18, CHTF8, CHTOP, CHUK, CHURC1, CHURC1-FNTB, CIAO1, CIAPIN1,CIART, CIB1, CIB2, CIB3, CIB4, CIC, CIDEA, CIDEB, CIDEC, CIITA, CILP,CILP2, CINP, CIPC, CIR1, CIRBP, CISD1, CISD2, CISD3, CISH, CIT, CITED1,CITED2, CITED4, CIZ1, CKAP2, CKAP2L, CKAP4, CKAP5, CKB, CKLF,CKLF-CMTM1, CKM, CKMT1A, CKMT1B, CKMT2, CKS1B, CKS2, CLASP1, CLASP2,CLASRP, CLC, CLCA1, CLCA2, CLCA4, CLCC1, CLCF1, CLCN1, CLCN2, CLCN3,CLCN4, CLCN5, CLCN6, CLCN7, CLCNKA, CLCNKB, CLDN1, CLDN10, CLDN11,CLDN12, CLDN14, CLDN15, CLDN16, CLDN17, CLDN18, CLDN19, CLDN2, CLDN20,CLDN22, CLDN23, CLDN24, CLDN25, CLDN3, CLDN34, CLDN4, CLDN5, CLDN6,CLDN7, CLDN8, CLDN9, CLDND1, CLDND2, CLEC10A, CLEC11A, CLEC12A, CLEC12B,CLEC14A, CLEC16A, CLEC17A, CLEC18A, CLEC18B, CLEC18C, CLEC19A, CLEC1A,CLECIB, CLEC20A, CLEC2A, CLEC2B, CLEC2D, CLEC2L, CLEC3A, CLEC3B, CLEC4A,CLEC4C, CLEC4D, CLEC4E, CLEC4F, CLEC4G, CLEC4M, CLEC5A, CLEC6A, CLEC7A,CLEC9A, CLECL1, CLGN, CLHC1, CLIC1, CLIC2, CLIC3, CLIC4, CLIC5, CLIC6,CLINT1, CLIP1, CLIP2, CLIP3, CLIP4, CLK1, CLK2, CLK3, CLK4, CLLU1,CLLU1OS, CLMN, CLMP, CLN3, CLN5, CLN6, CLN8, CLNK, CLNS1A, CLOCK, CLP1,CLPB, CLPP, CLPS, CLPSL1, CLPSL2, CLPTM1, CLPTM1L, CLPX, CLRN1, CLRN2,CLRN3, CLSPN, CLSTN1, CLSTN2, CLSTN3, CLTA, CLTB, CLTC, CLTCL1, CLU,CLUAP1, CLUH, CLUL1, CLVS1, CLVS2, CLYBL, CMA1, CMAS, CMBL, CMC1, CMC2,CMC4, CMIP, CMKLR1, CMPK1, CMPK2, CMSS1, CMTM1, CMTM2, CMTM3, CMTM4,CMTM5, CMTM6, CMTM7, CMTM8, CMTR1, CMTR2, CMYA5, CNBD1, CNBD2, CNBP,CNDP1, CNDP2, CNEP1R1, CNFN, CNGA1, CNGA2, CNGA3, CNGA4, CNGB1, CNGB3,CNIH1, CNIH2, CNIH3, CNIH4, CNKSR1, CNKSR2, CNKSR3, CNMD, CNN1, CNN2,CNN3, CNNM1, CNNM2, CNNM3, CNNM4, CNOT1, CNOT10, CNOT11, CNOT2, CNOT3,CNOT4, CNOT6, CNOT6L, CNOT7, CNOT8, CNOT9, CNP, CNPPD1, CNPY1, CNPY2,CNPY3, CNPY4, CNR1, CNR2, CNRIP1, CNST, CNTD1, CNTD2, CNTF, CNTFR,CNTLN, CNTN1, CNTN2, CNTN3, CNTN4, CNTN5, CNTN6, CNTNAP1, CNTNAP2,CNTNAP3, CNTNAP3B, CNTNAP4, CNTNAP5, CNTRL, CNTROB, COA1, COA3, COA4,COA5, COA6, COA7, COASY, COBL, COBLL1, COCH, COG1, COG2, COG3, COG4,COG5, COG6, COG7, COG8, COIL, COL10A1, COL11A1, COL11A2, COL12A1,COL13A1, COL14A1, COL15A1, COL16A1, COL17A1, COL18A1, COL19A1, COL1A1,COL1A2, COL20A1, COL21A1, COL22A1, COL23A1, COL24A1, COL25A1, COL26A1,COL27A1, COL28A1, COL2A1, COL3A1, COL4A1, COL4A2, COL4A3, COL4A3BP,COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, COL6A3,COL6A5, COL6A6, COL7A1, COL8A1, COL8A2, COL9A1, COL9A2, COL9A3, COLCA2,COLEC10, COLEC11, COLEC12, COLGALT1, COLGALT2, COLQ, COMMD1, COMMD10,COMMD2, COMMD3, COMMD3-BMI1, COMMD4, COMMD5, COMMD6, COMMD7, COMMD8,COMMD9, COMP, COMT, COMTD1, COPA, COPB1, COPB2, COPE, COPG1, COPG2,COPRS, COPS2, COPS3, COPS4, COPS5, COPS6, COPS7A, COPS7B, COPS8, COPS9,COPZ1, COPZ2, COQ10A, COQ10B, COQ2, COQ3, COQ4, COQ5, COQ6, COQ7, COQ8A,COQ8B, COQ9, CORIN, CORO1A, COROIB, COROIC, CORO2A, CORO2B, CORO6,CORO7, CORO7-PAM16, CORT, COTL1, COX10, COX11, COX14, COX15, COX16,COX17, COX18, COX19, COX20, COX4I1, COX4I2, COXSA, COXSB, COX6A1,COX6A2, COX6B1, COX6B2, COX6C, COX7A1, COX7A2, COX7A2L, COX7B, COX7B2,COX7C, COX8A, COX8C, CP, CPA1, CPA2, CPA3, CPA4, CPA5, CPA6, CPAMD8,CPB1, CPB2, CPD, CPE, CPEB1, CPEB2, CPEB3, CPEB4, CPED1, CPLX1, CPLX2,CPLX3, CPLX4, CPM, CPN1, CPN2, CPNE1, CPNE2, CPNE3, CPNE4, CPNE5, CPNE6,CPNE7, CPNE8, CPNE9, CPO, CPOX, CPPED1, CPQ, CPS1, CPSF1, CPSF2, CPSF3,CPSF4, CPSF4L, CPSF6, CPSF7, CPT1A, CPT1B, CPT1C, CPT2, CPTP, CPVL,CPXCR1, CPXM1, CPXM2, CPZ, CR1, CR1L, CR2, CR354443.1, CR354443.2,CR388407.3, CR547123.3, CR753842.1, CR753845.2, CR759815.2, CR788250.1,CR847794.2, CR854858.1, CR933783.3, CR936239.1, CRABP1, CRABP2, CRACR2A,CRACR2B, CRADD, CRAMP1, CRAT, CRB1, CRB2, CRB3, CRBN, CRCP, CRCT1,CREB1, CREB3, CREB3L1, CREB3L2, CREB3L3, CREB3L4, CREB5, CREBBP, CREBL2,CREBRF, CREBZF, CREG1, CREG2, CRELD1, CRELD2, CREM, CRH, CRHBP, CRHR1,CRHR2, CRIM1, CRIP1, CRIP2, CRIP3, CRIPT, CRISP1, CRISP2, CRISP3,CRISPLD1, CRISPLD2, CRK, CRKL, CRLF1, CRLF2, CRLF3, CRLS1, CRMP1,CRNKL1, CRNN, CROCC, CROCC2, CROT, CRP, CRTAC1, CRTAM, CRTAP, CRTC1,CRTC2, CRTC3, CRX, CRY1, CRY2, CRYAA, CRYAB, CRYBA1, CRYBA2, CRYBA4,CRYBB1, CRYBB2, CRYBB3, CRYBG1, CRYBG2, CRYBG3, CRYGA, CRYGB, CRYGC,CRYGD, CRYGN, CRYGS, CRYL1, CRYM, CRYZ, CRYZL1, CS, CSAD, CSAG1, CSAG2,CSAG3, CSDC2, CSDE1, CSE1L, CSF1, CSF1R, CSF2, CSF2RA, CSF2RB, CSF3,CSF3R, CSGALNACT1, CSGALNACT2, CSH1, CSH2, CSHL1, CSK, CSMD1, CSMD2,CSMD3, CSN1S1, CSN2, CSN3, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G1,CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CSNK2A3, CSNK2B, CSPG4, CSPG5,CSPP1, CSRNP1, CSRNP2, CSRNP3, CSRP1, CSRP2, CSRP3, CST1, CST11, CST2,CST3, CST4, CST5, CST6, CST7, CST8, CST9, CST9L, CSTA, CSTB, CSTF1,CSTF2, CSTF2T, CSTF3, CSTL1, CT45A1, CT45A10, CT45A2, CT45A3, CT45A5,CT45A6, CT45A7, CT45A8, CT45A9, CT476828.1, CT476828.10, CT476828.11,CT476828.12, CT476828.13, CT476828.14, CT476828.15, CT476828.16,CT476828.17, CT476828.18, CT476828.19, CT476828.2, CT476828.20,CT476828.21, CT476828.22, CT476828.3, CT476828.4, CT476828.5,CT476828.6, CT476828.7, CT476828.8, CT476828.9, CT47A1, CT47A10,CT47A11, CT47A12, CT47A2, CT47A3, CT47A4, CT47A5, CT47A6, CT47A7,CT47A8, CT47A9, CT47B1, CT55, CT62, CT83, CTAG1A, CTAG1B, CTAG2, CTAGE1,CTAGE15, CTAGE4, CTAGE5, CTAGE6, CTAGE8, CTAGE9, CTBP1, CTBP2, CTBS,CTC1, CTCF, CTCFL, CTDNEP1, CTDP1, CTDSP1, CTDSP2, CTDSPL, CTDSPL2,CTF1, CTGF, CTH, CTHRC1, CTIF, CTLA4, CTNNA1, CTNNA2, CTNNA3, CTNNAL1,CTNNB1, CTNNBIP1, CTNNBL1, CTNND1, CTNND2, CTNS, CTPS1, CTPS2, CTR9,CTRB1, CTRB2, CTRC, CTRL, CTSA, CTSB, CTSC, CTSD, CTSE, CTSF, CTSG,CTSH, CTSK, CTSL, CTSO, CTSS, CTSV, CTSW, CTSZ, CTTN, CTTNBP2,CTTNBP2NL, CTU1, CTU2, CTXN1, CTXN2, CTXN3, CTXND1, CU464060.1,CU633846.1, CU633980.1, CU633980.2, CU639417.1, CU639417.2, CUBN,CUEDC1, CUEDC2, CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5, CUL7, CUL9, CUTA,CUTC, CUX1, CUX2, CUZD1, CWC15, CWC22, CWC25, CWC27, CWF19L1, CWF19L2,CWH43, CX3CL1, CX3CR1, CXADR, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13,CXCL14, CXCL16, CXCL17, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, CXCL9, CXCR1,CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXorf21, CXorf36, CXorf38, CXorf40A,CXorf40B, CXorf49, CXorf49B, CXorf51A, CXorf51B, CXorf56, CXorf57,CXorf58, CXorf65, CXorf66, CXorf67, CXXC1, CXXC4, CXXC5, CYB561,CYB561A3, CYB561D1, CYB561D2, CYB5A, CYB5B, CYB5D1, CYB5D2, CYB5R1,CYB5R2, CYB5R3, CYB5R4, CYB5RL, CYBA, CYBB, CYBRD1, CYC1, CYCS, CYFIP1,CYFIP2, CYGB, CYHR1, CYLC1, CYLC2, CYLD, CYP11A1, CYP11B1, CYP11B2,CYP17A1, CYP19A1, CYP1A1, CYP1A2, CYP1B1, CYP20A1, CYP21A2, CYP24A1,CYP26A1, CYP26B1, CYP26C1, CYP27A1, CYP27B1, CYP27C1, CYP2A13, CYP2A6,CYP2A7, CYP2B6, CYP2C18, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2D7,CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1, CYP39A1, CYP3A4,CYP3A43, CYP3A5, CYP3A7, CYP3A7-CYP3A51P, CYP46A1, CYP4A11, CYP4A22,CYP4B1, CYP4F11, CYP4F12, CYP4F2, CYP4F22, CYP4F3, CYP4F8, CYP4V2,CYP4X1, CYP4Z1, CYP51A1, CYP7A1, CYP7B1, CYP8B1, CYR61, CYS1, CYSLTR1,CYSLTR2, CYSRT1, CYSTM1, CYTH1, CYTH2, CYTH3, CYTH4, CYTIP, CYTL1,CYYR1, D2HGDH, DAAM1, DAAM2, DAB1, DAB2, DAB2IP, DACH1, DACH2, DACT1,DACT2, DACT3, DAD1, DAG1, DAGLA, DAGLB, DALRD3, DAND5, DAO, DAOA, DAP,DAP3, DAPK1, DAPK2, DAPK3, DAPL1, DAPP1, DARS, DARS2, DAW1, DAXX, DAZ1,DAZ2, DAZ3, DAZ4, DAZAP1, DAZAP2, DAZL, DBF4, DBF4B, DBH, DBI, DBN1,DBNDD1, DBNDD2, DBNL, DBP, DBR1, DBT, DBX1, DBX2, DCAF1, DCAF10, DCAF11,DCAF12, DCAF12L1, DCAF12L2, DCAF13, DCAF15, DCAF16, DCAF17, DCAF4,DCAF4L1, DCAF4L2, DCAF5, DCAF6, DCAF7, DCAF8, DCAF8L1, DCAF8L2, DCAKD,DCANP1, DCBLD1, DCBLD2, DCC, DCD, DCDC1, DCDC2, DCDC2B, DCDC2C, DCHS1,DCHS2, DCK, DCLK1, DCLK2, DCLK3, DCLRE1A, DCLRE1B, DCLRE1C, DCN, DCP1A,DCP1B, DCP2, DCPS, DCST1, DCST2, DCSTAMP, DCT, DCTD, DCTN1, DCTN2,DCTN3, DCTN4, DCTN5, DCTN6, DCTPP1, DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4,DCUN1D5, DCX, DCXR, DDA1, DDAH1, DDAH2, DDB1, DDB2, DDC, DDHD1, DDHD2,DDI1, DDI2, DDIAS, DDIT3, DDIT4, DDIT4L, DDN, DDO, DDOST, DDR1, DDR2,DDRGK1, DDT, DDTL, DDX1, DDX10, DDX11, DDX17, DDX18, DDX19A, DDX19B,DDX20, DDX21, DDX23, DDX24, DDX25, DDX27, DDX28, DDX31, DDX39A, DDX39B,DDX3X, DDX3Y, DDX4, DDX41, DDX42, DDX43, DDX46, DDX47, DDX49, DDX5,DDX50, DDX51, DDX52, DDX53, DDX54, DDX55, DDX56, DDX58, DDX59, DDX6,DDX60, DDX60L, DEAF1, DEC1, DECR1, DECR2, DEDD, DEDD2, DEF6, DEF8,DEFA1, DEFA1B, DEFA3, DEFA4, DEFA5, DEFA6, DEFB1, DEFB103A, DEFB103B,DEFB104A, DEFB104B, DEFB105A, DEFB105B, DEFB106A, DEFB106B, DEFB107A,DEFB107B, DEFB108B, DEFB110, DEFB112, DEFB113, DEFB114, DEFB115,DEFB116, DEFB118, DEFB119, DEFB121, DEFB123, DEFB124, DEFB125, DEFB126,DEFB127, DEFB128, DEFB129, DEFB130A, DEFB130B, DEFB131A, DEFB131B,DEFB132, DEFB133, DEFB134, DEFB135, DEFB136, DEFB4A, DEFB4B, DEGS1,DEGS2, DEK, DENND1A, DENND1B, DENND1C, DENND2A, DENND2C, DENND2D,DENND3, DENND4A, DENND4B, DENND4C, DENND5A, DENND5B, DENND6A, DENND6B,DENR, DEPDC1, DEPDC1B, DEPDC4, DEPDC5, DEPDC7, DEPTOR, DERA, DERL1,DERL2, DERL3, DES, DESI1, DESI2, DET1, DEUP1, DEXI, DFFA, DFFB, DFNA5,DFNB59, DGAT1, DGAT2, DGAT2L6, DGCR2, DGCR6, DGCR6L, DGCR8, DGKA, DGKB,DGKD, DGKE, DGKG, DGKH, DGKI, DGKK, DGKQ, DGKZ, DGUOK, DHCR24, DHCR7,DHDDS, DHDH, DHFR, DHFR2, DHH, DHODH, DHPS, DHRS1, DHRS11, DHRS12,DHRS13, DHRS2, DHRS3, DHRS4, DHRS4L2, DHRS7, DHRS7B, DHRS7C, DHRS9,DHRSX, DHTKD1, DHX15, DHX16, DHX29, DHX30, DHX32, DHX33, DHX34, DHX35,DHX36, DHX37, DHX38, DHX40, DHX57, DHX58, DHX8, DHX9, DIABLO, DIAPH1,DIAPH2, DIAPH3, DICER1, DIDO1, DIEXF, DIMT1, DIO1, DIO2, DIO3, DIP2A,DIP2B, DIP2C, DIRAS1, DIRAS2, DIRAS3, DIRC1, DIRC2, DIRC3, DIS3, DIS3L,DIS3L2, DISC1, DISP1, DISP2, DISP3, DIXDC1, DKC1, DKK1, DKK2, DKK3,DKK4, DKKL1, DLAT, DLC1, DLD, DLEC1, DLEU7, DLG1, DLG2, DLG3, DLG4,DLG5, DLGAP1, DLGAP2, DLGAP3, DLGAP4, DLGAP5, DLK1, DLK2, DLL1, DLL3,DLL4, DLST, DLX1, DLX2, DLX3, DLX4, DLX5, DLX6, DMAC1, DMAC2, DMAP1,DMBT1, DMBX1, DMC1, DMD, DMGDH, DMKN, DMP1, DMPK, DMRT1, DMRT2, DMRT3,DMRTA1, DMRTA2, DMRTB1, DMRTC1, DMRTC1B, DMRTC2, DMTF1, DMTN, DMWD,DMXL1, DMXL2, DNA2, DNAAF1, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAH1,DNAH10, DNAH10OS, DNAH11, DNAH12, DNAH14, DNAH17, DNAH2, DNAH3, DNAH5,DNAH6, DNAH7, DNAH8, DNAH9, DNAI1, DNAI2, DNAJA1, DNAJA2, DNAJA3,DNAJA4, DNAJB1, DNAJB11, DNAJB12, DNAJB13, DNAJB14, DNAJB2, DNAJB4,DNAJB5, DNAJB6, DNAJB7, DNAJB8, DNAJB9, DNAJC1, DNAJC10, DNAJC11,DNAJC12, DNAJC13, DNAJC14, DNAJC15, DNAJC16, DNAJC17, DNAJC18, DNAJC19,DNAJC2, DNAJC21, DNAJC22, DNAJC24, DNAJC25, DNAJC25-GNG10, DNAJC27,DNAJC28, DNAJC3, DNAJC30, DNAJC4, DNAJC5, DNAJC5B, DNAJC5G, DNAJC6,DNAJC7, DNAJC8, DNAJC9, DNAL1, DNAL4, DNALI1, DNASE1, DNASE1L1,DNASE1L2, DNASE1L3, DNASE2, DNASE2B, DND1, DNER, DNHD1, DNLZ, DNM1,DNM1L, DNM2, DNM3, DNMBP, DNMT1, DNMT3A, DNMT3B, DNMT3L, DNPEP, DNPH1,DNTT, DNTTIP1, DNTTIP2, DOC2A, DOC2B, DOCK1, DOCK10, DOCK11, DOCK2,DOCK3, DOCK4, DOCK5, DOCK6, DOCK7, DOCK8, DOCK9, DOHH, DOK1, DOK2, DOK3,DOK4, DOK5, DOK6, DOK7, DOLK, DOLPP1, DONSON, DOPEY1, DOPEY2, DOT1L,DPAGT1, DPCD, DPCR1, DPEP1, DPEP2, DPEP3, DPF1, DPF2, DPF3, DPH1, DPH2,DPH3, DPH5, DPH6, DPH7, DPM1, DPM2, DPM3, DPP10, DPP3, DPP4, DPP6, DPP7,DPP8, DPP9, DPPA2, DPPA3, DPPA4, DPPA5, DPRX, DPT, DPY19L1, DPY19L2,DPY19L3, DPY19L4, DPY30, DPYD, DPYS, DPYSL2, DPYSL3, DPYSL4, DPYSL5,DQX1, DR1, DRAM1, DRAM2, DRAP1, DRAXIN, DRC1, DRC3, DRC7, DRD1, DRD2,DRD3, DRD4, DRD5, DRG1, DRG2, DRGX, DRICH1, DROSHA, DRP2, DSC1, DSC2,DSC3, DSCAM, DSCAML1, DSCC1, DSCR3, DSCR4, DSCR8, DSE, DSEL, DSG1, DSG2,DSG3, DSG4, DSN1, DSP, DSPP, DST, DSTN, DSTYK, DTD1, DTD2, DTHD1, DTL,DTNA, DTNB, DTNBP1, DTWD1, DTWD2, DTX1, DTX2, DTX3, DTX3L, DTX4, DTYMK,DUOX1, DUOX2, DUOXA1, DUOXA2, DUPD1, DUS1L, DUS2, DUS3L, DUS4L, DUSP1,DUSP10, DUSP11, DUSP12, DUSP13, DUSP14, DUSP15, DUSP16, DUSP18, DUSP19,DUSP2, DUSP21, DUSP22, DUSP23, DUSP26, DUSP27, DUSP28, DUSP3, DUSP4,DUSP5, DUSP6, DUSP7, DUSP8, DUSP9, DUT, DUX4, DUXA, DUXB, DVL1, DVL2,DVL3, DWORF, DXO, DYDC1, DYDC2, DYM, DYNAP, DYNC1H1, DYNC1I1, DYNC1I2,DYNC1LI1, DYNC1LI2, DYNC2H1, DYNC2LI1, DYNLL1, DYNLL2, DYNLRB1, DYNLRB2,DYNLT1, DYNLT3, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, DYSF, DYTN, DZANK1,DZIP1, DZIP1L, DZIP3, E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, E2F7, E2F8,E4F1, EAF1, EAF2, EAPP, EARS2, EBAG9, EBF1, EBF2, EBF3, EBF4, EBI3,EBLN1, EBLN2, EBNA1BP2, EBP, EBPL, ECD, ECE1, ECE2, ECEL1, ECH1, ECHDC1,ECHDC2, ECHDC3, ECHS1, ECI1, ECI2, ECM1, ECM2, ECSCR, ECSIT, ECT2,ECT2L, EDA, EDA2R, EDAR, EDARADD, EDC3, EDC4, EDDM13, EDDM3A, EDDM3B,EDEM1, EDEM2, EDEM3, EDF1, EDIL3, EDN1, EDN2, EDN3, EDNRA, EDNRB, EDRF1,EEA1, EED, EEF1A1, EEF1A2, EEF1AKMT1, EEF1AKMT2, EEF1AKMT3, EEF1B2,EEF1D, EEF1E1, EEF1E1-BLOC1S5, EEF1G, EEF2, EEF2K, EEF2KMT, EEFSEC,EEPD1, EFCAB1, EFCAB10, EFCAB11, EFCAB12, EFCAB13, EFCAB14, EFCAB2,EFCAB3, EFCAB5, EFCAB6, EFCAB7, EFCAB8, EFCAB9, EFCC1, EFEMP1, EFEMP2,EFHB, EFHC1, EFHC2, EFHD1, EFHD2, EFL1, EFNA1, EFNA2, EFNA3, EFNA4,EFNA5, EFNB1, EFNB2, EFNB3, EFR3A, EFR3B, EFS, EFTUD2, EGF, EGFL6,EGFL7, EGFL8, EGFLAM, EGFR, EGLN1, EGLN2, EGLN3, EGR1, EGR2, EGR3, EGR4,EHBP1, EHBP1L1, EHD1, EHD2, EHD3, EHD4, EHF, EHHADH, EHMT1, EHMT2, E124,EID1, EID2, EID2B, EID3, EIF1, EIF1AD, EIF1AX, EIF1AY, EIF1B, EIF2A,EIF2AK1, EIF2AK2, EIF2AK3, EIF2AK4, EIF2B1, EIF2B2, EIF2B3, EIF2B4,EIF2B5, EIF2D, EIF2S1, EIF2S2, EIF2S3, EIF3A, EIF3B, EIF3C, EIF3CL,EIF3D, EIF3E, EIF3F, EIF3G, EIF3H, EIF3I, EIF3J, EIF3K, EIF3L, EIF3M,EIF4A1, EIF4A2, EIF4A3, EIF4B, EIF4E, EIF4E1B, EIF4E2, EIF4E3, EIF4EBP1,EIF4EBP2, EIF4EBP3, EIF4ENIF1, EIF4G1, EIF4G2, EIF4G3, EIF4H, EIF5,EIF5A, EIF5A2, EIF5AL1, EIF5B, EIF6, EIPR1, ELAC1, ELAC2, ELANE, ELAVL1,ELAVL2, ELAVL3, ELAVL4, ELF1, ELF2, ELF3, ELF4, ELF5, ELFN1, ELFN2,ELK1, ELK3, ELK4, ELL, ELL2, ELL3, ELMO1, ELMO2, ELMO3, ELMOD1, ELMOD2,ELMOD3, ELMSAN1, ELN, ELOA, ELOA2, ELOA3, ELOA3B, ELOA3C, ELOA3D, ELOB,ELOC, ELOF1, ELOVL1, ELOVL2, ELOVL3, ELOVL4, ELOVL5, ELOVL6, ELOVL7,ELP1, ELP2, ELP3, ELP4, ELP5, ELP6, ELSPBP1, EMB, EMC1, EMC10, EMC2,EMC3, EMC4, EMC6, EMC7, EMC8, EMC9, EMCN, EMD, EME1, EME2, EMG1, EMID1,EMILIN1, EMILIN2, EMILIN3, EML1, EML2, EML3, EML4, EML5, EML6, EMP1,EMP2, EMP3, EMSY, EMX1, EMX2, EN1, EN2, ENAH, ENAM, ENC1, ENDOD1, ENDOG,ENDOU, ENDOV, ENG, ENGASE, ENHO, ENKD1, ENKUR, ENO1, ENO2, ENO3, ENO4,ENOPH1, ENOSF1, ENOX1, ENOX2, ENPEP, ENPP1, ENPP2, ENPP3, ENPP4, ENPP5,ENPP6, ENPP7, ENSA, ENTHD1, ENTPD1, ENTPD2, ENTPD3, ENTPD4, ENTPD5,ENTPD6, ENTPD7, ENTPD8, ENY2, EOGT, EOMES, EP300, EP400, EPAS1, EPB41,EPB41L1, EPB41L2, EPB41L3, EPB41L4A, EPB41L4B, EPB41L5, EPB42, EPC1,EPC2, EPCAM, EPDR1, EPG5, EPGN, EPHA1, EPHA10, EPHA2, EPHA3, EPHA4,EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, EPHX1,EPHX2, EPHX3, EPHX4, EPM2A, EPM2AIP1, EPN1, EPN2, EPN3, EPO, EPOP, EPOR,EPPIN, EPPIN-WFDC6, EPPK1, EPRS, EPS15, EPS15L1, EPS8, EPS8L1, EPS8L2,EPS8L3, EPSTI1, EPX, EPYC, EQTN, ERAL1, ERAP1, ERAP2, ERAS, ERBB2,ERBB3, ERBB4, ERBIN, ERC1, ERC2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5,ERCC6, ERCC6L, ERCC6L2, ERCC8, EREG, ERF, ERFE, ERG, ERG28, ERGIC1,ERGIC2, ERGIC3, ERH, ERI1, ERI2, ERI3, ERICH1, ERICH2, ERICH3, ERICH4,ERICH5, ERICH6, ERICH6B, ERLEC1, ERLIN1, ERLIN2, ERMAP, ERMARD, ERMN,ERMP1, ERN1, ERN2, ERO1A, ERO1B, ERP27, ERP29, ERP44, ERRFI1, ERV3-1,ERVFRD-1, ERVMER34-1, ERVV-1, ERVV-2, ERVW-1, ESAM, ESCO1, ESCO2, ESD,ESF1, ESM1, ESPL1, ESPN, ESPNL, ESR1, ESR2, ESRP1, ESRP2, ESRRA, ESRRB,ESRRG, ESS2, ESX1, ESYT1, ESYT2, ESYT3, ETAA1, ETDA, ETDB, ETDC, ETF1,ETFA, ETFB, ETFBKMT, ETFDH, ETFRF1, ETHE1, ETNK1, ETNK2, ETNPPL, ETS1,ETS2, ETV1, ETV2, ETV3, ETV3L, ETV4, ETV5, ETV6, ETV7, EVA1A, EVA1B,EVA1C, EVC, EVC2, EVI2A, EVI2B, EVI5, EVI5L, EVL, EVPL, EVPLL, EVX1,EVX2, EWSR1, EXD1, EXD2, EXD3, EXO1, EXO5, EXOC1, EXOCIL, EXOC2, EXOC3,EXOC3L1, EXOC3L2, EXOC3L4, EXOC4, EXOC5, EXOC6, EXOC6B, EXOC7, EXOC8,EXOG, EXOSC1, EXOSC10, EXOSC2, EXOSC3, EXOSC4, EXOSC5, EXOSC6, EXOSC7,EXOSC8, EXOSC9, EXPH5, EXT1, EXT2, EXTL1, EXTL2, EXTL3, EYA1, EYA2,EYA3, EYA4, EYS, EZH1, EZH2, EZR, F10, F11, F11R, F12, F13A1, F13B, F2,F2R, F2RL1, F2RL2, F2RL3, F3, F5, F7, F8, F8A1, F8A2, F8A3, F9, FA2H,FAAH, FAAH2, FAAP100, FAAP20, FAAP24, FABP1, FABP12, FABP2, FABP3,FABP4, FABP5, FABP6, FABP7, FABP9, FADD, FADS1, FADS2, FADS3, FADS6,FAF1, FAF2, FAH, FAHD1, FAHD2A, FAHD2B, FAIM, FAIM2, FAM102A, FAM102B,FAM103A1, FAM104A, FAM104B, FAM105A, FAM106A, FAM107A, FAM107B, FAM109A,FAM109B, FAM110A, FAM110B, FAM110C, FAM110D, FAM111A, FAM111B, FAM114A1,FAM114A2, FAM117A, FAM117B, FAM118A, FAM118B, FAM120A, FAM120AOS,FAM120B, FAM120C, FAM122A, FAM122B, FAM122C, FAM124A, FAM124B, FAM126A,FAM126B, FAM129A, FAM129B, FAM129C, FAM131A, FAM131B, FAM131C, FAM133A,FAM133B, FAM135A, FAM135B, FAM136A, FAM13A, FAM13B, FAM13C, FAM149A,FAM149B1, FAM151A, FAM151B, FAM153A, FAM153B, FAM153C, FAM155A, FAM155B,FAM156A, FAM156B, FAM159A, FAM159B, FAM160A1, FAM160A2, FAM160B1,FAM160B2, FAM161A, FAM161B, FAM162A, FAM162B, FAM163A, FAM163B, FAM166A,FAM166B, FAM167A, FAM167B, FAM168A, FAM168B, FAM169A, FAM169B, FAM170A,FAM170B, FAM171A1, FAM171A2, FAM171B, FAM172A, FAM173A, FAM173B,FAM174A, FAM174B, FAM177A1, FAM177B, FAM178B, FAM180A, FAM180B, FAM181A,FAM181B, FAM182B, FAM183A, FAM184A, FAM184B, FAM185A, FAM186A, FAM186B,FAM187A, FAM187B, FAM189A1, FAM189A2, FAM189B, FAM192A, FAM193A,FAM193B, FAM196A, FAM196B, FAM198A, FAM198B, FAM199X, FAM19A1, FAM19A2,FAM19A3, FAM19A4, FAM19A5, FAM200A, FAM200B, FAM204A, FAM205A, FAM205C,FAM206A, FAM207A, FAM208A, FAM208B, FAM209A, FAM209B, FAM20A, FAM20B,FAM20C, FAM210A, FAM210B, FAM212A, FAM212B, FAM213A, FAM213B, FAM214A,FAM214B, FAM216A, FAM216B, FAM217A, FAM217B, FAM218A, FAM219A, FAM219B,FAM220A, FAM221A, FAM221B, FAM222A, FAM222B, FAM227A, FAM227B, FAM228A,FAM228B, FAM229A, FAM229B, FAM230A, FAM231A, FAM231B, FAM231C, FAM231D,FAM234A, FAM234B, FAM236A, FAM236B, FAM236C, FAM236D, FAM237A, FAM237B,FAM240A, FAM240B, FAM24A, FAM24B, FAM25A, FAM25C, FAM25G, FAM26D,FAM26E, FAM26F, FAM32A, FAM35A, FAM3A, FAM3B, FAM3C, FAM3D, FAM43A,FAM43B, FAM45A, FAM46A, FAM46B, FAM46C, FAM46D, FAM47A, FAM47B, FAM47C,FAM47E, FAM47E-STBD1, FAM49A, FAM49B, FAM50A, FAM50B, FAM53A, FAM53B,FAM53C, FAM57A, FAM57B, FAM58A, FAM60A, FAM69A, FAM69B, FAM69C, FAM71A,FAM71B, FAM71C, FAM71D, FAM71E1, FAM71E2, FAM71F1, FAM71F2, FAM72A,FAM72B, FAM72C, FAM72D, FAM76A, FAM76B, FAM78A, FAM78B, FAM81A, FAM81B,FAM83A, FAM83B, FAM83C, FAM83D, FAM83E, FAM83F, FAM83G, FAM83H, FAM84A,FAM84B, FAM86B1, FAM86B2, FAM86C1, FAM89A, FAM89B, FAM8A1, FAM90A1,FAM90A26, FAM91A1, FAM92A, FAM92B, FAM95C, FAM96A, FAM96B, FAM98A,FAM98B, FAM98C, FAM9A, FAM9B, FAM9C, FAN1, FANCA, FANCB, FANCC, FANCD2,FANCD2OS, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANK1, FAP, FAR1,FAR2, FARP1, FARP2, FARS2, FARSA, FARSB, FAS, FASLG, FASN, FASTK,FASTKD1, FASTKD2, FASTKD3, FASTKD5, FAT1, FAT2, FAT3, FAT4, FATE1, FAU,FAXC, FAXDC2, FBF1, FBL, FBLIM1, FBLL1, FBLN1, FBLN2, FBLN5, FBLN7,FBN1, FBN2, FBN3, FBP1, FBP2, FBRS, FBRSL1, FBXL12, FBXL13, FBXL14,FBXL15, FBXL16, FBXL17, FBXL18, FBXL19, FBXL2, FBXL20, FBXL22, FBXL3,FBXL4, FBXL5, FBXL6, FBXL7, FBXL8, FBXO10, FBXO11, FBX015, FBX016,FBX017, FBX018, FBXO2, FBXO21, FBXO22, FBXO24, FBXO25, FBXO27, FBXO28,FBXO3, FBXO30, FBXO31, FBXO32, FBXO33, FBXO34, FBXO36, FBXO38, FBXO39,FBXO4, FBXO40, FBXO41, FBXO42, FBXO43, FBXO44, FBXO45, FBXO46, FBXO47,FBXO48, FBXO5, FBXO6, FBXO7, FBXO8, FBXO9, FBXW10, FBXW11, FBXW12,FBXW2, FBXW4, FBXW5, FBXW7, FBXW8, FBXW9, FCAMR, FCAR, FCER1A, FCER1G,FCER2, FCF1, FCGBP, FCGR1A, FCGR1B, FCGR2A, FCGR2B, FCGR2C, FCGR3A,FCGR3B, FCGRT, FCHO1, FCHO2, FCHSD1, FCHSD2, FCMR, FCN1, FCN2, FCN3,FCRL1, FCRL2, FCRL3, FCRL4, FCRL5, FCRL6, FCRLA, FCRLB, FDCSP, FDFT1,FDPS, FDX1, FDX2, FDXACB1, FDXR, FECH, FEM1A, FEM1B, FEM1C, FEN1, FER,FER1L5, FER1L6, FERD3L, FERMT1, FERMT2, FERMT3, FES, FETUB, FEV, FEZ1,FEZ2, FEZF1, FEZF2, FFAR1, FFAR2, FFAR3, FFAR4, FGA, FGB, FGD1, FGD2,FGD3, FGD4, FGD5, FGD6, FGF1, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16,FGF17, FGF18, FGF19, FGF2, FGF20, FGF21, FGF22, FGF23, FGF3, FGF4, FGF5,FGF6, FGF7, FGF8, FGF9, FGFBP1, FGFBP2, FGFBP3, FGFR1, FGFR1OP,FGFR1OP2, FGFR2, FGFR3, FGFR4, FGFRL1, FGG, FGGY, FGL1, FGL2, FGR, FH,FHAD1, FHDC1, FHIT, FHL1, FHL2, FHL3, FHL5, FHOD1, FHOD3, FIBCD1, FIBIN,FIBP, FICD, FIG4, FIGLA, FIGN, FIGNL1, FIGNL2, FILTP1, FILIP1L, FIP1L1,FIS1, FITM1, FITM2, FIZ1, FJX1, FKBP10, FKBP11, FKBP14, FKBP15, FKBP1A,FKBP1B, FKBP1C, FKBP2, FKBP3, FKBP4, FKBP5, FKBP6, FKBP7, FKBP8, FKBP9,FKBPL, FKRP, FKTN, FLAD1, FLCN, FLG, FLG2, FLI1, FLII, FLNA, FLNB, FLNC,FLOT1, FLOT2, FLRT1, FLRT2, FLRT3, FLT1, FLT3, FLT3LG, FLT4, FLVCR1,FLVCR2, FLYWCH1, FLYWCH2, FMC1, FMN1, FMN2, FMNL1, FMNL2, FMNL3, FMO1,FMO2, FMO3, FMO4, FMO5, FMOD, FMR1, FMR1NB, FN1, FN3K, FN3KRP, FNBP1,FNBP1L, FNBP4, FNDC1, FNDC10, FNDC11, FNDC3A, FNDC3B, FNDC4, FNDC5,FNDC7, FNDC8, FNDC9, FNIP1, FNIP2, FNTA, FNTB, F0681492.1, F0681542.1,FOCAD, FOLH1, FOLR1, FOLR2, FOLR3, FOPNL, FOS, FOSB, FOSL1, FOSL2,FOXA1, FOXA2, FOXA3, FOXB1, FOXB2, FOXC1, FOXC2, FOXD1, FOXD2, FOXD3,FOXD4, FOXD4L1, FOXD4L3, FOXD4L4, FOXD4L5, FOXD4L6, FOXE1, FOXE3, FOXF1,FOXF2, FOXG1, FOXH1, FOXI1, FOXI2, FOXI3, FOXJ1, FOXJ2, FOXJ3, FOXK1,FOXK2, FOXL1, FOXL2, FOXL2NB, FOXM1, FOXN1, FOXN2, FOXN3, FOXN4, FOXO1,FOXO3, FOXO4, FOXO6, FOXP1, FOXP2, FOXP3, FOXP4, FOXQ1, FOXR1, FOXR2,FOXRED1, FOXRED2, FOXS1, FP236240.1, FP565260.1, FP565260.2, FP565260.3,FP565260.4, FP565260.6, FP565260.7, FP565324.1, FP565324.2, FPGS, FPGT,FPGT-TNNI3K, FPR1, FPR2, FPR3, FRA10AC1, FRAS1, FRAT1, FRAT2, FREM1,FREM2, FREM3, FRG1, FRG2, FRG2B, FRG2C, FRK, FRMD1, FRMD3, FRMD4A,FRMD4B, FRMD5, FRMD6, FRMD7, FRMD8, FRMPD1, FRMPD2, FRMPD3, FRMPD4,FRRS1, FRRS1L, FRS2, FRS3, FRY, FRYL, FRZB, FSBP, FSCB, FSCN1, FSCN2,FSCN3, FSD1, FSD1L, FSD2, FSHB, FSHR, FSIP1, FSIP2, FST, FSTL1, FSTL3,FSTL4, FSTL5, FTCD, FTCDNL1, FTH1, FTHL17, FTL, FTMT, FTO, FTSJ1, FTSJ3,FUBP1, FUBP3, FUCA1, FUCA2, FUK, FUNDC1, FUNDC2, FUOM, FURIN, FUS, FUT1,FUT10, FUT11, FUT2, FUT3, FUT4, FUT5, FUT6, FUT7, FUT8, FUT9, FUZ, FXN,FXR1, FXR2, FXYD1, FXYD2, FXYD3, FXYD4, FXYD5, FXYD6, FXYD6-FXYD2,FXYD7, FYB1, FYB2, FYCO1, FYN, FYTTD1, FZD1, FZD10, FZD2, FZD3, FZD4,FZD5, FZD6, FZD7, FZD8, FZD9, FZR1, GOS2, G2E3, G3BP1, G3BP2, G6PC,G6PC2, G6PC3, G6PD, GAA, GAB1, GAB2, GAB3, GAB4, GABARAP, GABARAPL1,GABARAPL2, GABBR1, GABBR2, GABPA, GABPB1, GABPB2, GABRA1, GABRA2,GABRA3, GABRA4, GABRA5, GABRA6, GABRB1, GABRB2, GABRB3, GABRD, GABRE,GABRG1, GABRG2, GABRG3, GABRP, GABRQ, GABRR1, GABRR2, GABRR3, GAD1,GAD2, GADD45A, GADD45B, GADD45G, GADD45GIP1, GADL1, GAGE1, GAGE10,GAGE12B, GAGE12C, GAGE12D, GAGE12E, GAGE12F, GAGE12G, GAGE12H, GAGE12J,GAGE13, GAGE2A, GAGE2E, GAK, GAL, GAL3ST1, GAL3ST2, GAL3ST3, GAL3ST4,GALC, GALE, GALK1, GALK2, GALM, GALNS, GALNT1, GALNT10, GALNT11,GALNT12, GALNT13, GALNT14, GALNT15, GALNT16, GALNT17, GALNT18, GALNT2,GALNT3, GALNT4, GALNT5, GALNT6, GALNT7, GALNT8, GALNT9, GALNTL5,GALNTL6, GALP, GALR1, GALR2, GALR3, GALT, GAMT, GAN, GANAB, GANC, GAP43,GAPDH, GAPDHS, GAPT, GAPVD1, GAR1, GAREM1, GAREM2, GARNL3, GARS, GART,GAS1, GAS2, GAS2L1, GAS2L2, GAS2L3, GAS6, GAS7, GAS8, GAST, GATA1,GATA2, GATA3, GATA4, GATA5, GATA6, GATAD1, GATAD2A, GATAD2B, GATB, GATC,GATD1, GATM, GATS, GBA, GBA2, GBA3, GBE1, GBF1, GBGT1, GBP1, GBP2, GBP3,GBP4, GBP5, GBP6, GBP7, GBX1, GBX2, GC, GCA, GCAT, GCC1, GCC2, GCDH,GCFC2, GCG, GCGR, GCH1, GCHFR, GCK, GCKR, GCLC, GCLM, GCM1, GCM2, GCN1,GCNA, GCNT1, GCNT2, GCNT3, GCNT4, GCNT7, GCOM1, GCSAM, GCSAML, GCSH,GDA, GDAP1, GDAP1L1, GDAP2, GDE1, GDF1, GDF10, GDF11, GDF15, GDF2, GDF3,GDF5, GDF5OS, GDF6, GDF7, GDF9, GDI1, GDI2, GDNF, GDPD1, GDPD2, GDPD3,GDPD4, GDPD5, GDPGP1, GEM, GEMIN2, GEMIN4, GEMIN5, GEMIN6, GEMIN7,GEMIN8, GEN1, GET4, GFAP, GFER, GFI1, GFI1B, GFM1, GFM2, GFOD1, GFOD2,GFPT1, GFPT2, GFRA1, GFRA2, GFRA3, GFRA4, GFRAL, GFY, GGA1, GGA2, GGA3,GGACT, GGCT, GGCX, GGH, GGN, GGNBP2, GGPS1, GGT1, GGT2, GGT5, GGT6,GGT7, GGTLC1, GGTLC2, GGTLC3, GH1, GH2, GHDC, GHITM, GHR, GHRH, GHRHR,GHRL, GHSR, GID4, GID8, GIF, GIGYF1, GIGYF2, GIMAP1, GIMAP1-GIMAP5,GIMAP2, GIMAP4, GIMAP5, GIMAP6, GIMAP7, GIMAP8, GIMD1, GIN1, GINM1,GINS1, GINS2, GINS3, GINS4, GIP, GIPC1, GIPC2, GIPC3, GIPR, GIT1, GIT2,GJA1, GJA10, GJA3, GJA4, GJA5, GJA8, GJA9, GJB1, GJB2, GJB3, GJB4, GJB5,GJB6, GJB7, GJC1, GJC2, GJC3, GJD2, GJD3, GJD4, GJE1, GK, GK2, GK3P,GK5, GKAP1, GKN1, GKN2, GLA, GLB1, GLB1L, GLB1L2, GLB1L3, GLCCI1, GLCE,GLDC, GLDN, GLE1, GLG1, GLI1, GLI2, GLI3, GLI4, GLIPR1, GLIPR1L1,GLIPR1L2, GLIPR2, GLIS1, GLIS2, GLIS3, GLMN, GLMP, GLO1, GLOD4, GLOD5,GLP1R, GLP2R, GLRA1, GLRA2, GLRA3, GLRA4, GLRB, GLRX, GLRX2, GLRX3,GLRX5, GLS, GLS2, GLT1D1, GLT6D1, GLT8D1, GLT8D2, GLTP, GLTPD2, GLUD1,GLUD2, GLUL, GLYAT, GLYATL1, GLYATL1P3, GLYATL2, GLYATL3, GLYCTK, GLYR1,GM2A, GMCL1, GMDS, GMEB1, GMEB2, GMFB, GMFG, GMIP, GML, GMNC, GMNN,GMPPA, GMPPB, GMPR, GMPR2, GMPS, GNA11, GNA12, GNA13, GNA14, GNA15,GNAI1, GNAI2, GNAI3, GNAL, GNAO1, GNAQ, GNAS, GNAT1, GNAT2, GNAT3, GNAZ,GNB1, GNB1L, GNB2, GNB3, GNB4, GNB5, GNE, GNG10, GNG11, GNG12, GNG13,GNG14, GNG2, GNG3, GNG4, GNG5, GNG7, GNG8, GNGT1, GNGT2, GNL1, GNL2,GNL3, GNL3L, GNLY, GNMT, GNPAT, GNPDA1, GNPDA2, GNPNAT1, GNPTAB, GNPTG,GNRH1, GNRH2, GNRHR, GNS, GOLGA1, GOLGA2, GOLGA3, GOLGA4, GOLGA5,GOLGA6A, GOLGA6B, GOLGA6C, GOLGA6D, GOLGA6L1, GOLGA6L10, GOLGA6L2,GOLGA6L22, GOLGA6L4, GOLGA6L6, GOLGA6L7P, GOLGA6L9, GOLGA7, GOLGA7B,GOLGA8A, GOLGA8B, GOLGA8F, GOLGA8G, GOLGA8H, GOLGA8J, GOLGA8K, GOLGA8M,GOLGA8N, GOLGA80, GOLGA8Q, GOLGA8R, GOLGA8S, GOLGA8T, GOLGB1, GOLIM4,GOLM1, GOLPH3, GOLPH3L, GOLT1A, GOLT1B, GON4L, GON7, GOPC, GORAB,GORASP1, GORASP2, GOSR1, GOSR2, GOT1, GOT1L1, GOT2, GP1BA, GP1BB, GP2,GP5, GP6, GP9, GPA33, GPAA1, GPALPP1, GPAM, GPANK1, GPAT2, GPAT3, GPAT4,GPATCH1, GPATCH11, GPATCH2, GPATCH2L, GPATCH3, GPATCH4, GPATCH8, GPBAR1,GPBP1, GPBP1L1, GPC1, GPC2, GPC3, GPC4, GPC5, GPC6, GPCPD1, GPD1, GPD1L,GPD2, GPER1, GPHA2, GPHB5, GPHN, GPI, GPIBP1, GPKOW, GPLD1, GPM6A,GPM6B, GPN1, GPN2, GPN3, GPNMB, GPR1, GPR101, GPR107, GPR108, GPR119,GPR12, GPR132, GPR135, GPR137, GPR137B, GPR137C, GPR139, GPR141, GPR142,GPR143, GPR146, GPR148, GPR149, GPR15, GPR150, GPR151, GPR152, GPR153,GPR155, GPR156, GPR157, GPR158, GPR160, GPR161, GPR162, GPR17, GPR171,GPR173, GPR174, GPR176, GPR179, GPR18, GPR180, GPR182, GPR183, GPR19,GPR20, GPR21, GPR22, GPR25, GPR26, GPR27, GPR3, GPR31, GPR32, GPR33,GPR34, GPR35, GPR37, GPR37L1, GPR39, GPR4, GPR42, GPR45, GPR50, GPR52,GPR55, GPR6, GPR61, GPR62, GPR63, GPR65, GPR68, GPR75, GPR75-ASB3,GPR78, GPR82, GPR83, GPR84, GPR85, GPR87, GPR88, GPR89A, GPR89B,GPRASP1, GPRASP2, GPRC5A, GPRC5B, GPRC5C, GPRC5D, GPRC6A, GPRIN1,GPRIN2, GPRIN3, GPS1, GPS2, GPSM1, GPSM2, GPSM3, GPT, GPT2, GPX1, GPX2,GPX3, GPX4, GPX5, GPX6, GPX7, GPX8, GRAMD1A, GRAMD1B, GRAMD1C, GRAMD2A,GRAMD2B, GRAMD4, GRAP, GRAP2, GRAPL, GRASP, GRB10, GRB14, GRB2, GRB7,GREB1, GREB1L, GREM1, GREM2, GRHL1, GRHL2, GRHL3, GRHPR, GRIA1, GRIA2,GRIA3, GRIA4, GRID1, GRID2, GRID2IP, GRIFIN, GRIK1, GRIK2, GRIK3, GRIK4,GRIK5, GRIN1, GRIN2A, GRIN2B, GRIN2C, GRIN2D, GRIN3A, GRIN3B, GRINA,GRIP1, GRIP2, GRIPAP1, GRK1, GRK2, GRK3, GRK4, GRK5, GRK6, GRK7, GRM1,GRM2, GRM3, GRM4, GRM5, GRM6, GRM7, GRM8, GRN, GRP, GRPEL1, GRPEL2,GRPR, GRSF1, GRTP1, GRWD1, GRXCR1, GRXCR2, GSAP, GSC, GSC2, GSDMA,GSDMB, GSDMC, GSDMD, GSE1, GSG1, GSG1L, GSG1L2, GSK3A, GSK3B, GSKIP,GSN, GSPT1, GSPT2, GSR, GSS, GSTA1, GSTA2, GSTA3, GSTA4, GSTA5, GSTCD,GSTK1, GSTM1, GSTM2, GSTM3, GSTM4, GSTM5, GSTO1, GSTG2, GSTP1, GSTT1,GSTT2, GSTT2B, GSTTP1, GSTZ1, GSX1, GSX2, GTDC1, GTF2A1, GTF2A1L,GTF2A2, GTF2B, GTF2E1, GTF2E2, GTF2F1, GTF2F2, GTF2H1, GTF2H2, GTF2H2C,GTF2H2C_2, GTF2H3, GTF2H4, GTF2H5, GTF2I, GTF2IRD1, GTF2IRD2, GTF2IRD2B,GTF3A, GTF3C1, GTF3C2, GTF3C3, GTF3C4, GTF3C5, GTF3C6, GTPBP1, GTPBP10,GTPBP2, GTPBP3, GTPBP4, GTPBP6, GTPBP8, GTSE1, GTSF1, GTSF1L,GU182339.1, GU182339.3, GU182343.1, GU182343.2, GU182345.1, GU182345.2,GU182347.1, GU182351.2, GU182352.2, GU182353.1, GU182355.1, GU182355.2,GU182355.3, GU182357.1, GU182357.3, GU182359.1, GU182359.2, GUCA1A,GUCA1B, GUCA1C, GUCA2A, GUCA2B, GUCD1, GUCY1A2, GUCY1A3, GUCY1B3,GUCY2C, GUCY2D, GUCY2F, GUF1, GUK1, GULP1, GUSB, GVQW2, GXYLT1, GXYLT2,GYG1, GYG2, GYPA, GYPB, GYPC, GYPE, GYS1, GYS2, GZF1, GZMA, GZMB, GZMH,GZMK, GZMM, H1F0, H1FNT, H1FOO, H1FX, H2AFB1, H2AFB2, H2AFB3, H2AFJ,H2AFV, H2AFX, H2AFY, H2AFY2, H2AFZ, H2BFM, H2BFS, H2BFWT, H3F3A, H3F3B,H3F3C, H6PD, HAAO, HABP2, HABP4, HACD1, HACD2, HACD3, HACD4, HACE1,HACL1, HADH, HADHA, HADHB, HAGH, HAGHL, HAL, HAMP, HAND1, HAND2, HAO1,HAG2, HAP1, HAPLN1, HAPLN2, HAPLN3, HAPLN4, HARBI1, HARS, HARS2, HAS1,HAS2, HAS3, HASPIN, HAT1, HAUS1, HAUS2, HAUS3, HAUS4, HAUS5, HAUS6,HAUS7, HAUS8, HAVCR1, HAVCR2, HAX1, HBA1, HBA2, HBB, HBD, HBE1, HBEGF,HBG1, HBG2, HBM, HBP1, HBQ1, HBS1L, HBZ, HCAR1, HCAR2, HCAR3, HCCS,HCFC1, HCFC1R1, HCFC2, HCK, HCLS1, HCN1, HCN2, HCN3, HCN4, HCRT, HCRTR1,HCRTR2, HCST, HDAC1, HDAC10, HDAC11, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6,HDAC7, HDAC8, HDAC9, HDC, HDDC2, HDDC3, HDGF, HDGFL1, HDGFL2, HDGFL3,HDHD2, HDHD3, HDHD5, HDLBP, HDX, HEATR1, HEATR3, HEATR4, HEATR5A,HEATR5B, HEATR6, HEATR9, HEBP1, HEBP2, HECA, HECTD1, HECTD2, HECTD3,HECTD4, HECW1, HECW2, HEG1, HELB, HELLS, HELQ, HELT, HELZ, HELZ2, HEMGN,HEMK1, HENMT1, HEPACAM, HEPACAM2, HEPH, HEPHL1, HEPN1, HERC1, HERC2,HERC3, HERC4, HERC5, HERC6, HERPUD1, HERPUD2, HES1, HES2, HES3, HES4,HES5, HES6, HES7, HESX1, HEXA, HEXB, HEXDC, HEXIM1, HEXIM2, HEY1, HEY2,HEYL, HFE, HFE2, HFM1, HGD, HGF, HGFAC, HGH1, HGNC:18790, HGNC:24955,HGS, HGSNAT, HHAT, HHATL, HHEX, HHIP, HHIPL1, HHIPL2, HHLA1, HHLA2,HHLA3, HIBADH, HIBCH, HIC1, HIC2, HID1, HIF1A, HIF1AN, HIF3A, HIGD1A,HIGD1B, HIGD1C, HIGD2A, HIGD2B, HIKESH1, HILPDA, HINFP, HINT1, HINT2,HINT3, HIP1, HIP1R, HIPK1, HIPK2, HIPK3, HIPK4, HIRA, HIRIP3, HIST1H1A,HIST1H1B, HIST1H1C, HIST1H1D, HIST1H1E, HIST1H1T, HIST1H2AA, HIST1H2AB,HIST1H2AC, HIST1H2AD, HIST1H2AE, HIST1H2AG, HIST1H2AH, HIST1H2AI,HIST1H2AJ, HIST1H2AK, HIST1H2AL, HIST1H2AM, HIST1H2BA, HIST1H2BB,HIST1H2BC, HIST1H2BD, HIST1H2BE, HIST1H2BF, HIST1H2BG, HIST1H2BH,HIST1H2BI, HIST1H2BJ, HIST1H2BK, HIST1H2BL, HIST1H2BM, HIST1H2BN,HIST1H2BO, HIST1H3A, HIST1H3B, HIST1H3C, HIST1H3D, HIST1H3E, HIST1H3F,HIST1H3G, HIST1H3H, HIST1H3I, HIST1H3J, HIST1H4A, HIST1H4B, HIST1H4C,HIST1H4D, HIST1H4E, HIST1H4F, HIST1H4G, HIST1H4H, HIST1H4I, HIST1H4J,HIST1H4K, HIST1H4L, HIST2H2AA3, HIST2H2AA4, HIST2H2AB, HIST2H2AC,HIST2H2BE, HIST2H2BF, HIST2H3A, HIST2H3C, HIST2H3D, HIST2H3PS2,HIST2H4A, HIST2H4B, HIST3H2A, HIST3H2BB, HIST3H3, HIST4H4, HIVEP1,HIVEP2, HIVEP3, HJURP, HK1, HK2, HK3, HKDC1, HKR1, HLA-A, HLA-B, HLA-C,HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1,HLA-DQA2, HLA-DQB1, HLA-DQB2, HLA-DRA, HLA-DRB1, HLA-DRB3, HLA-DRB4,HLA-DRB5, HLA-E, HLA-F, HLA-G, HLCS, HLF, HLTF, HLX, HM13, HM190170.1,HMBOX1, HMBS, HMCES, HMCN1, HMCN2, HMG20A, HMG20B, HMGA1, HMGA2, HMGB1,HMGB2, HMGB3, HMGB4, HMGCL, HMGCLL1, HMGCR, HMGCS1, HMGCS2, HMGN1,HMGN2, HMGN3, HMGN4, HMGN5, HMGXB3, HMGXB4, HMHB1, HMMR, HMOX1, HMOX2,HMSD, HMX1, HMX2, HMX3, HNF1A, HNF1B, HNF4A, HNF4G, HNMT, HNRNPA0,HNRNPA1, HNRNPA1L2, HNRNPA2B1, HNRNPA3, HNRNPAB, HNRNPC, HNRNPCL1,HNRNPCL2, HNRNPCL3, HNRNPCL4, HNRNPD, HNRNPDL, HNRNPF, HNRNPH1, HNRNPH2,HNRNPH3, HNRNPK, HNRNPL, HNRNPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1,HNRNPUL2, HNRNPUL2-BSCL2, HOGA1, HOMER1, HOMER2, HOMER3, HOMEZ, HOOK1,HOOK2, HOOK3, HOPX, HORMAD1, HORMAD2, HOXA1, HOXA10, HOXA11, HOXA13,HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXB1, HOXB13, HOXB2,HOXB3, HOXB4, HOXB5, HOXB6, HOXB7, HOXB8, HOXB9, HOXC10, HOXC11, HOXC12,HOXC13, HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXD1, HOXD10, HOXD11,HOXD12, HOXD13, HOXD3, HOXD4, HOXD8, HOXD9, HP, HP1BP3, HPCA, HPCAL1,HPCAL4, HPD, HPDL, HPF1, HPGD, HPGDS, HPN, HPR, HPRT1, HPS1, HPS3, HPS4,HPS5, HPS6, HPSE, HPSE2, HPX, HR, HRAS, HRASLS, HRASLS2, HRASLS5, HRC,HRCT1, HRG, HRH1, HRH2, HRH3, HRH4, HRK, HRNR, HS1BP3, HS2ST1, HS3ST1,HS3ST2, HS3ST3A1, HS3ST3B1, HS3ST4, HS3ST5, HS3ST6, HS6ST1, HS6ST2,HS6ST3, HSBP1, HSBP1L1, HSCB, HSD11B1, HSD11B1L, HSD11B2, HSD17B1,HSD17B10, HSD17B11, HSD17B12, HSD17B13, HSD17B14, HSD17B2, HSD17B3,HSD17B4, HSD17B6, HSD17B7, HSD17B8, HSD3B1, HSD3B2, HSD3B7, HSDL1,HSDL2, HSF1, HSF2, HSF2BP, HSF4, HSF5, HSFX1, HSFX2, HSFX3, HSFX4,HSFY1, HSFY2, HSH2D, HSP90AA1, HSP90AB1, HSP90B1, HSPA12A, HSPA12B,HSPA13, HSPA14, HSPA1A, HSPA1B, HSPA1L, HSPA2, HSPA4, HSPA4L, HSPA5,HSPA6, HSPA8, HSPA9, HSPB1, HSPB11, HSPB2, HSPB2-C11orf52, HSPB3, HSPB6,HSPB7, HSPB8, HSPB9, HSPBAP1, HSPBP1, HSPD1, HSPE1, HSPE1-MOB4, HSPG2,HSPH1, HTATIP2, HTATSF1, HTD2, HTN1, HTN3, HTR1A, HTR1B, HTR1D, HTR1E,HTR1F, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR3C, HTR3D, HTR3E, HTR4,HTR5A, HTR6, HTR7, HTRA1, HTRA2, HTRA3, HTRA4, HTT, HUNK, HUS1, HUS1B,HUWE1, HVCN1, HYAL1, HYAL2, HYAL3, HYAL4, HYDIN, HYI, HYKK, HYLS1,HYOU1, HYPK, HYPM, IAH1, IAPP, IARS, IARS2, IBA57, IBSP, IBTK, ICA1,ICA1L, ICAM1, ICAM2, ICAM3, ICAM4, ICAM5, ICE1, ICE2, ICK, ICMT, ICOS,ICOSLG, ID1, ID2, ID3, ID4, IDE, IDH1, IDH2, IDH3A, IDH3B, IDH3G, IDI1,IDI2, IDNK, IDO1, IDO2, IDS, IDUA, IER2, IER3, IER3IP1, IER5, IER5L,IFFO1, IFF02, IFI16, IFI27, IFI27L1, IFI27L2, IFI30, IFI35, IFI44,IFI44L, IFI6, IFIH1, IFIT1, IFIT1B, IFIT2, IFIT3, IFIT5, IFITM1,IFITM10, IFITM2, IFITM3, IFITM5, IFNA1, IFNA10, IFNA13, IFNA14, IFNA16,IFNA17, IFNA2, IFNA21, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNAR1,IFNAR2, IFNB1, IFNE, IFNG, IFNGR1, IFNGR2, IFNK, IFNL1, IFNL2, IFNL3,IFNL4, IFNLR1, IFNW1, IFRD1, IFRD2, IFT122, IFT140, IFT172, IFT20,IFT22, IFT27, IFT43, IFT46, IFT52, IFT57, IFT74, IFT80, IFT81, IFT88,IGBP1, IGDCC3, IGDCC4, IGF1, IGF1R, IGF2, IGF2BP1, IGF2BP2, IGF2BP3,IGF2R, IGFALS, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGFBP7,IGFBPL1, IGFL1, IGFL2, IGFL3, IGFL4, IGFLR1, IGFN1, IGHA1, IGHA2, IGHD,IGHD1-1, IGHD1-14, IGHD1-20, IGHD1-26, IGHD1-7, IGHD1OR15-1A,IGHD1OR15-1B, IGHD2-15, IGHD2-2, IGHD2-21, IGHD2-8, IGHD2OR15-2A,IGHD2OR15-2B, IGHD3-10, IGHD3-16, IGHD3-22, IGHD3-3, IGHD3-9,IGHD30R15-3A, IGHD30R15-3B, IGHD4-11, IGHD4-17, IGHD4-23, IGHD4-4,IGHD40R15-4A, IGHD40R15-4B, IGHD5-12, IGHD5-18, IGHD5-24, IGHD5-5,IGHD50R15-5A, IGHD50R15-5B, IGHD6-13, IGHD6-19, IGHD6-25, IGHD6-6,IGHD7-27, IGHE, IGHG1, IGHG2, IGHG3, IGHG4, IGHJ1, IGHJ2, IGHJ3, IGHJ4,IGHJ5, IGHJ6, IGHM, IGHMBP2, IGHV1-18, IGHV1-2, IGHV1-24, IGHV1-3,IGHV1-45, IGHV1-46, IGHV1-58, IGHV1-69, IGHV1OR15-1, IGHV1OR15-9,IGHV1OR21-1, IGHV2-26, IGHV2-5, IGHV2-70, IGHV2OR16-5, IGHV3-11,IGHV3-13, IGHV3-15, IGHV3-16, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-30,IGHV3-33, IGHV3-35, IGHV3-38, IGHV3-43, IGHV3-48, IGHV3-49, IGHV3-53,IGHV3-64, IGHV3-66, IGHV3-7, IGHV3-72, IGHV3-73, IGHV3-74, IGHV30R15-7,IGHV30R16-10, IGHV30R16-12, IGHV30R16-13, IGHV30R16-8, IGHV30R16-9,IGHV4-28, IGHV4-31, IGHV4-34, IGHV4-39, IGHV4-4, IGHV4-59, IGHV4-61,IGHV4OR15-8, IGHV5-51, IGHV6-1, IGHV7-81, IGIP, IGKC, IGKJ1, IGKJ2,IGKJ3, IGKJ4, IGKJ5, IGKV1-12, IGKV1-16, IGKV1-17, IGKV1-27, IGKV1-33,IGKV1-37, IGKV1-39, IGKV1-5, IGKV1-6, IGKV1-8, IGKV1-9, IGKV1D-12,IGKV1D-13, IGKV1D-16, IGKV1D-17, IGKV1D-33, IGKV1D-37, IGKV1D-39,IGKV1D-42, IGKV1D-43, IGKV1D-8, IGKV1OR2-108, IGKV2-24, IGKV2-28,IGKV2-30, IGKV2-40, IGKV2D-24, IGKV2D-26, IGKV2D-28, IGKV2D-29,IGKV2D-30, IGKV2D-40, IGKV3-11, IGKV3-15, IGKV3-20, IGKV3-7, IGKV3D-11,IGKV3D-15, IGKV3D-20, IGKV3D-7, IGKV3OR2-268, IGKV4-1, IGKV5-2,IGKV6-21, IGKV6D-21, IGKV6D-41, IGLC1, IGLC2, IGLC3, IGLC7, IGLJ1,IGLJ2, IGLJ3, IGLJ4, IGLJ5, IGLJ6, IGLJ7, IGLL1, IGLL5, IGLON5,IGLV10-54, IGLV11-55, IGLV1-36, IGLV1-40, IGLV1-44, IGLV1-47, IGLV1-50,IGLV1-51, IGLV2-11, IGLV2-14, IGLV2-18, IGLV2-23, IGLV2-33, IGLV2-8,IGLV3-1, IGLV3-10, IGLV3-12, IGLV3-16, IGLV3-19, IGLV3-21, IGLV3-22,IGLV3-25, IGLV3-27, IGLV3-32, IGLV3-9, IGLV4-3, IGLV4-60, IGLV4-69,IGLV5-37, IGLV5-45, IGLV5-48, IGLV5-52, IGLV6-57, IGLV7-43, IGLV7-46,IGLV8-61, IGLV9-49, IGSF1, IGSF10, IGSF11, IGSF21, IGSF22, IGSF23,IGSF3, IGSF5, IGSF6, IGSF8, IGSF9, IGSF9B, IHH, IK, IKBIP, IKBKB, IKBKE,IKBKG, IKZF1, IKZF2, IKZF3, IKZF4, IKZF5, IL10, IL10RA, IL10RB, IL11,IL11RA, IL12A, IL12B, IL12RB1, IL12RB2, IL13, IL13RA1, IL13RA2, IL15,IL15RA, IL16, IL17A, IL17B, IL17C, IL17D, IL17F, IL17RA, IL17RB, IL17RC,IL17RD, IL17RE, IL17REL, IL18, IL18BP, IL18R1, IL18RAP, IL19, IL1A,IL1B, IL1F10, IL1R1, IL1R2, IL1RAP, IL1RAPL1, IL1RAPL2, IL1RL1, IL1RL2,IL1RN, IL2, IL20, IL20RA, IL20RB, IL21, IL21R, IL22, IL22RA1, IL22RA2,IL23A, IL23R, IL24, IL25, IL26, IL27, IL27RA, IL2RA, IL2RB, IL2RG, IL3,IL31, IL31RA, IL32, IL33, IL34, IL36A, IL36B, IL36G, IL36RN, IL37,IL3RA, IL4, IL4I1, IL4R, IL5, IL5RA, IL6, IL6R, IL6ST, IL7, IL7R, IL9,IL9R, ILDR1, ILDR2, ILF2, ILF3, ILK, ILKAP, ILVBL, IMMP1L, IMMP2L, IMMT,IVP3, IMP4, IMPA1, IMPA2, IMPACT, IMPAD1, ITMPDH1, IMPDH2, IMPG1, VIPG2,INA, INAFM1, INAFM2, INAVA, INCA1, INCENP, INF2, ING1, ING2, ING3, ING4,ING5, INHA, INHBA, INHBB, INHBC, INHBE, INIP, INMT, INMT-MINDY4, INO80,INO80B, INO80B-WBP1, INO80C, INO80D, INO80E, INPP1, INPP4A, INPP4B,INPP5A, INPP5B, INPP5D, INPP5E, INPP5F, INPP5J, INPP5K, INPPL1, INS,INSC, INSIG1, INSIG2, INS-IGF2, INSL3, INSL4, INSL5, INSL6, INSM1,INSM2, INSR, INSRR, INTS1, INTS10, INTS11, INTS12, INTS13, INTS14,INTS2, INTS3, INTS4, INTS5, INTS6, INTS6L, INTS7, INTS8, INTS9, INTU,INVS, IP6K1, IP6K2, IP6K3, IPCEF1, IPMK, IPO11, IPO13, IPO4, IPO5, IPO7,IPO8, IPO9, IPP, IPPK, IQANK1, IQCA1, IQCA1L, IQCB1, IQCC, IQCD, IQCE,IQCF1, IQCF2, IQCF3, IQCF5, IQCF6, IQCG, IQCH, IQCJ, IQCJ-SCHIP1, IQCK,IQCM, IQGAP1, IQGAP2, IQGAP3, IQSEC1, IQSEC2, IQSEC3, IQUB, IRAK1,IRAK1BP1, IRAK2, IRAK3, IRAK4, IREB2, IRF1, IRF2, IRF2BP1, IRF2BP2,IRF2BPL, IRF3, IRF4, IRF5, IRF6, IRF7, IRF8, IRF9, IRGC, IRGM, IRGQ,IRS1, IRS2, IRS4, IRX1, IRX2, IRX3, IRX4, IRX5, IRX6, ISCA1, ISCA2,ISCU, ISG15, ISG20, ISG20L2, ISL1, ISL2, ISLR, ISLR2, ISM1, ISM2, ISOC1,ISOC2, ISPD, IST1, ISX, ISY1, ISY1-RAB43, ISYNA1, ITCH, ITFG1, ITFG2,ITGA1, ITGA10, ITGA11, ITGA2, ITGA2B, ITGA3, ITGA4, ITGA5, ITGA6, ITGA7,ITGA8, ITGA9, ITGAD, ITGAE, ITGAL, ITGAM, ITGAV, ITGAX, ITGB1, ITGB1BP1,ITGB1BP2, ITGB2, ITGB3, ITGB3BP, ITGB4, ITGB5, ITGB6, ITGB7, ITGB8,ITGBL1, ITIH1, ITIH2, ITIH3, ITIH4, ITIH5, ITIH6, ITK, ITLN1, ITLN2,ITM2A, ITM2B, ITM2C, ITPA, ITPK1, ITPKA, ITPKB, ITPKC, ITPR1, ITPR2,ITPR3, ITPRIP, ITPRIPL1, ITPRIPL2, ITSN1, ITSN2, IVD, IVL, IVNS1ABP,IWS1, IYD, IZUMO1, IZUMO1R, IZUMO2, IZUMO3, IZUMO4, JADE1, JADE2, JADE3,JAG1, JAG2, JAGN1, JAK1, JAK2, JAK3, JAKMIP1, JAKMIP2, JAKMIP3, JAM2,JAM3, JAML, JARID2, JAZF1, JCAD, JCHAIN, JDP2, JKAMP, JMJD1C, JMJD4,JMJD6, JMJD7, JMJD7-PLA2G4B, JMJD8, JMY, JOSD1, JOSD2, JPH1, JPH2, JPH3,JPH4, JPT1, JPT2, JRK, JRKL, JSRP1, JTB, JUN, JUNB, JUND, JUP, KAAG1,KALRN, KANK1, KANK2, KANK3, KANK4, KANSL1, KANSLIL, KANSL2, KANSL3,KANTR, KARS, KAT14, KAT2A, KAT2B, KAT5, KAT6A, KAT6B, KAT7, KAT8,KATNA1, KATNAL1, KATNAL2, KATNB1, KATNBL1, KAZALD1, KAZN, KBTBD11,KBTBD11-OT1, KBTBD12, KBTBD13, KBTBD2, KBTBD3, KBTBD4, KBTBD6, KBTBD7,KBTBD8, KCMF1, KCNA1, KCNA10, KCNA2, KCNA3, KCNA4, KCNA5, KCNA7, KCNAB1,KCNAB2, KCNAB3, KCNB1, KCNB2, KCNC1, KCNC2, KCNC3, KCNC4, KCND1, KCND2,KCND3, KCNE1, KCNE1B, KCNE2, KCNE3, KCNE4, KCNE5, KCNF1, KCNG1, KCNG2,KCNG3, KCNG4, KCNH1, KCNH2, KCNH3, KCNH4, KCNH5, KCNH6, KCNH7, KCNH8,KCNIP1, KCNIP2, KCNIP3, KCNIP4, KCNJ1, KCNJ10, KCNJ11, KCNJ12, KCNJ13,KCNJ14, KCNJ15, KCNJ16, KCNJ18, KCNJ2, KCNJ3, KCNJ4, KCNJ5, KCNJ6,KCNJ8, KCNJ9, KCNK1, KCNK10, KCNK12, KCNK13, KCNK15, KCNK16, KCNK17,KCNK18, KCNK2, KCNK3, KCNK4, KCNK5, KCNK6, KCNK7, KCNK9, KCNMA1, KCNMB1,KCNMB2, KCNMB3, KCNMB4, KCNN1, KCNN2, KCNN3, KCNN4, KCNQ1, KCNQ2, KCNQ3,KCNQ4, KCNQ5, KCNRG, KCNS1, KCNS2, KCNS3, KCNT1, KCNT2, KCNU1, KCNV1,KCNV2, KCP, KCTD1, KCTD10, KCTD11, KCTD12, KCTD13, KCTD14, KCTD15,KCTD16, KCTD17, KCTD18, KCTD19, KCTD2, KCTD20, KCTD21, KCTD3, KCTD4,KCTD5, KCTD6, KCTD7, KCTD8, KCTD9, KDELC1, KDELC2, KDELR1, KDELR2,KDELR3, KDF1, KDM1A, KDM1B, KDM2A, KDM2B, KDM3A, KDM3B, KDM4A, KDM4B,KDM4C, KDM4D, KDM4E, KDM4F, KDM5A, KDM5B, KDM5C, KDM5D, KDM6A, KDM6B,KDM7A, KDM8, KDR, KDSR, KEAP1, KEL, KERA, KF459570.1, KHDC1, KHDC1L,KHDC3L, KHDRBS1, KHDRBS2, KHDRBS3, KHK, KHNYN, KHSRP, KIAA0040,KIAA0100, KIAA0141, KIAA0232, KIAA0319, KIAA0319L, KIAA0355, KIAA0368,KIAA0391, KIAA0408, KIAA0513, KIAA0556, KIAA0586, KIAA0753, KIAA0825,KIAA0895, KIAA0895L, KIAA0907, KIAA0930, KIAA1024, KIAA1024L, KIAA1107,KIAA1109, KIAA1143, KIAA1147, KIAA1161, KIAA1191, KIAA1210, KIAA1211,KIAA1211L, KIAA1217, KIAA1257, KIAA1324, KIAA1324L, KIAA1328, KIAA1456,KIAA1468, KIAA1522, KIAA1524, KIAA1549, KIAA1549L, KIAA1551, KIAA1586,KIAA1614, KIAA1644, KIAA1671, KIAA1683, KIAA1755, KIAA1841, KIAA1958,KIAA2012, KIAA2013, KIAA2026, KIDINS220, KIF11, KIF12, KIF13A, KIF13B,KIF14, KIF15, KIF16B, KIF17, KIF18A, KIF18B, KIF19, KIF1A, KIF1B,KIF1BP, KIF1C, KIF20A, KIF20B, KIF21A, KIF21B, KIF22, KIF23, KIF24,KIF25, KIF26A, KIF26B, KIF27, KIF2A, KIF2B, KIF2C, KIF3A, KIF3B, KIF3C,KIF4A, KIF4B, KIF5A, KIF5B, KIF5C, KIF6, KIF7, KIF9, KIFAP3, KIFC1,KIFC2, KIFC3, KIN, KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5A,KIR2DL5B, KIR2DP1, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1,KIR3DL2, KIR3DL3, KIR3DP1, KIR3DS1, KIR3DX1, KIRREL1, KIRREL2, KIRREL3,KISS1, KISS1R, KIT, KITLG, KIZ, KL, KLB, KLC1, KLC2, KLC3, KLC4, KLF1,KLF10, KLF11, KLF12, KLF13, KLF14, KLF15, KLF16, KLF17, KLF18, KLF2,KLF3, KLF4, KLF5, KLF6, KLF7, KLF8, KLF9, KLHDC1, KLHDC10, KLHDC2,KLHDC3, KLHDC4, KLHDC7A, KLHDC7B, KLHDC8A, KLHDC8B, KLHDC9, KLHL1,KLHL10, KLHL11, KLHL12, KLHL13, KLHL14, KLHL15, KLHL17, KLHL18, KLHL2,KLHL20, KLHL21, KLHL22, KLHL23, KLHL24, KLHL25, KLHL26, KLHL28, KLHL29,KLHL3, KLHL30, KLHL31, KLHL32, KLHL33, KLHL34, KLHL35, KLHL36, KLHL38,KLHL4, KLHL40, KLHL41, KLHL42, KLHL5, KLHL6, KLHL7, KLHL8, KLHL9, KLK1,KLK10, KLK11, KLK12, KLK13, KLK14, KLK15, KLK2, KLK3, KLK4, KLK5, KLK6,KLK7, KLK8, KLK9, KLKB1, KLLN, KLRB1, KLRC1, KLRC2, KLRC3, KLRC4,KLRC4-KLRK1, KLRD1, KLRF1, KLRF2, KLRG1, KLRG2, KLRK1, KMO, KMT2A,KMT2B, KMT2C, KMT2D, KMT2E, KMT5A, KMT5B, KMT5C, KNCN, KNDC1, KNG1,KNL1, KNOP1, KNSTRN, KNTC1, KP420437.1, KP420437.2, KP420437.3,KP420439.1, KP420440.1, KP420440.2, KP420440.3, KP420440.4, KP420440.5,KP420440.6, KP420440.7, KP420440.8, KP420440.9, KP420441.1, KP420441.2,KP420441.3, KP420441.4, KP420441.5, KP420442.2, KP420442.3, KP420443.1,KP420444.1, KP420444.2, KP420444.3, KP420444.4, KP420444.5, KP420444.6,KP420444.7, KP420446.1, KP420446.2, KPNA1, KPNA2, KPNA3, KPNA4, KPNA5,KPNA6, KPNA7, KPNB1, KPRP, KPTN, KRAS, KRBA1, KRBA2, KRBOX1, KRBOX4,KRCC1, KREMEN1, KREMEN2, KRI1, KRIT1, KRR1, KRT1, KRT10, KRT12, KRT13,KRT14, KRT15, KRT16, KRT17, KRT18, KRT19, KRT2, KRT20, KRT222, KRT23,KRT24, KRT25, KRT26, KRT27, KRT28, KRT3, KRT31, KRT32, KRT33A, KRT33B,KRT34, KRT35, KRT36, KRT37, KRT38, KRT39, KRT4, KRT40, KRT5, KRT6A,KRT6B, KRT6C, KRT7, KRT71, KRT72, KRT73, KRT74, KRT75, KRT76, KRT77,KRT78, KRT79, KRT8, KRT80, KRT81, KRT82, KRT83, KRT84, KRT85, KRT86,KRT9, KRTAP10-1, KRTAP10-10, KRTAP10-11, KRTAP10-12, KRTAP10-2,KRTAP10-3, KRTAP10-4, KRTAP10-5, KRTAP10-6, KRTAP10-7, KRTAP10-8,KRTAP10-9, KRTAP1-1, KRTAP11-1, KRTAP12-1, KRTAP12-2, KRTAP12-3,KRTAP12-4, KRTAP1-3, KRTAP13-1, KRTAP13-2, KRTAP13-3, KRTAP13-4,KRTAP1-4, KRTAP1-5, KRTAP15-1, KRTAP16-1, KRTAP17-1, KRTAP19-1,KRTAP19-2, KRTAP19-3, KRTAP19-4, KRTAP19-5, KRTAP19-6, KRTAP19-7,KRTAP19-8, KRTAP20-1, KRTAP20-2, KRTAP20-3, KRTAP20-4, KRTAP2-1,KRTAP21-1, KRTAP21-2, KRTAP21-3, KRTAP2-2, KRTAP22-1, KRTAP22-2,KRTAP2-3, KRTAP23-1, KRTAP2-4, KRTAP24-1, KRTAP25-1, KRTAP26-1,KRTAP27-1, KRTAP29-1, KRTAP3-1, KRTAP3-2, KRTAP3-3, KRTAP4-1, KRTAP4-11,KRTAP4-12, KRTAP4-16, KRTAP4-2, KRTAP4-3, KRTAP4-4, KRTAP4-5, KRTAP4-6,KRTAP4-7, KRTAP4-8, KRTAP4-9, KRTAP5-1, KRTAP5-10, KRTAP5-11, KRTAP5-2,KRTAP5-3, KRTAP5-4, KRTAP5-5, KRTAP5-6, KRTAP5-7, KRTAP5-8, KRTAP5-9,KRTAP6-1, KRTAP6-2, KRTAP6-3, KRTAP7-1, KRTAP8-1, KRTAP9-1, KRTAP9-2,KRTAP9-3, KRTAP9-4, KRTAP9-6, KRTAP9-7, KRTAP9-8, KRTAP9-9, KRTCAP2,KRTCAP3, KRTDAP, KSR1, KSR2, KTI12, KTN1, KU645196.1, KU645196.2,KU645196.3, KU645196.4, KU645196.5, KU645196.6, KU645196.7, KU645196.8,KU645196.9, KU645197.1, KU645197.2, KU645197.3, KU645197.4, KU645197.5,KU645198.1, KXD1, KY, KYAT1, KYAT3, KYNU, L1CAM, L1TD1, L2HGDH,L34079.1, L3HYPDH, L3MBTL1, L3MBTL2, L3MBTL3, L3MBTL4, LACC1, LACRT,LACTB, LACTB2, LACTBL1, LAD1, LAG3, LAGE3, LAIR1, LAIR2, LALBA, LAMA1,LAMA2, LAMA3, LAMA4, LAMA5, LAMB1, LAMB2, LAMB3, LAMB4, LAMC1, LAMC2,LAMC3, LAMP1, LAMP2, LAMP3, LAMP5, LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4,LAMTOR5, LANCL1, LANCL2, LANCL3, LAP3, LAPTM4A, LAPTM4B, LAPTM5, LARGE1,LARGE2, LARP1, LARP1B, LARP4, LARP4B, LARP6, LARP7, LARS, LARS2, LAS1L,LASP1, LAT, LAT2, LATS1, LATS2, LAX1, LAYN, LBH, LBHD1, LBP, LBR, LBX1,LBX2, LCA5, LCA5L, LCAT, LCE1A, LCE1B, LCE1C, LCE1D, LCE1E, LCE1F,LCE2A, LCE2B, LCE2C, LCE2D, LCE3A, LCE3B, LCE3C, LCE3D, LCE3E, LCE4A,LCE5A, LCE6A, LCK, LCLAT1, LCMT1, LCMT2, LCN1, LCN10, LCN12, LCN15,LCN2, LCN6, LCN8, LCN9, LCNL1, LCOR, LCORL, LCP1, LCP2, LCT, LCTL, LDAH,LDB1, LDB2, LDB3, LDHA, LDHAL6A, LDHAL6B, LDHB, LDHC, LDHD, LDLR,LDLRAD1, LDLRAD2, LDLRAD3, LDLRAD4, LDLRAP1, LDOC1, LEAP2, LECT2, LEF1,LEFTY1, LEFTY2, LEKR1, LELP1, LEMD1, LEMD2, LEMD3, LENEP, LENG1, LENG8,LENG9, LEO1, LEP, LEPR, LEPROT, LEPROTL1, LETM1, LETM2, LETMD1, LEUTX,LEXM, LFNG, LGALS1, LGALS12, LGALS13, LGALS14, LGALS16, LGALS2, LGALS3,LGALS3BP, LGALS4, LGALS7, LGALS7B, LGALS8, LGALS9, LGALS9B, LGALS9C,LGALSL, LGI1, LGI2, LGI3, LGI4, LGMN, LGR4, LGR5, LGR6, LGSN, LHB,LHCGR, LHFPL1, LHFPL2, LHFPL3, LHFPL4, LHFPL5, LHFPL6, LHPP, LHX1, LHX2,LHX3, LHX4, LHX5, LHX6, LHX8, LHX9, LIAS, LIF, LIFR, LIG1, LIG3, LIG4,LILRA1, LILRA2, LILRA3, LILRA4, LILRA5, LILRA6, LILRB1, LILRB2, LILRB3,LILRB4, LILRB5, LIM2, LIMA1, LIMCH1, LIMD1, LIMD2, LIME1, LIMK1, LIMK2,LIMS1, LIMS2, LIMS3, LIMS4, LIN28A, LIN28B, LIN37, LIN52, LIN54, LIN7A,LIN7B, LIN7C, LIN9, LINC00094, LINC00116, LINC00282, LINC00672,LINC00675, LINC00694, LINC00854, LINC00890, LINC00959, LINC01125,LINC01556, LINC02210-CRHR1, LINGO1, LING02, LINGO3, LINGO4, LINS1, LIPA,LIPC, LIPE, LIPF, LIPG, LIPH, LIPI, LIPJ, LIPK, LIPM, LIPN, LIPT1,LIPT2, LITAF, LIX1, LIX1L, LKAAEAR1, LLGL1, LLGL2, LLPH, LMAN1, LMAN1L,LMAN2, LMAN2L, LMBR1, LMBR1L, LMBRD1, LMBRD2, LMCD1, LMF1, LMF2, LMLN,LMNA, LMNB1, LMNB2, LMNTD1, LMNTD2, LMO1, LMO2, LMO3, LMO4, LMO7,LMO7DN, LMOD1, LMOD2, LMOD3, LMTK2, LMTK3, LMX1A, LMX1B, LNP1, LNPEP,LNPK, LNX1, LNX2, LO000005.1, LONP1, LONP2, LONRF1, LONRF2, LONRF3, LOR,LOX, LOXHD1, LOXL1, LOXL2, LOXL3, LOXL4, LPA, LPAR1, LPAR2, LPAR3,LPAR4, LPAR5, LPAR6, LPCAT1, LPCAT2, LPCAT3, LPCAT4, LPGAT1, LPIN1,LPIN2, LPIN3, LPL, LPO, LPP, LPXN, LRAT, LRBA, LRCH1, LRCH2, LRCH3,LRCH4, LRCOL1, LRFN1, LRFN2, LRFN3, LRFN4, LRFN5, LRG1, LRGUK, LRIF1,LRIG1, LRIG2, LRIG3, LRIT1, LRIT2, LRIT3, LRMDA, LRMP, LRP1, LRP10,LRP11, LRP12, LRP1B, LRP2, LRP2BP, LRP3, LRP4, LRP5, LRP5L, LRP6, LRP8,LRPAP1, LRPPRC, LRR1, LRRC1, LRRC10, LRRC10B, LRRC14, LRRC14B, LRRC15,LRRC17, LRRC18, LRRC19, LRRC2, LRRC20, LRRC23, LRRC24, LRRC25, LRRC26,LRRC27, LRRC28, LRRC29, LRRC3, LRRC30, LRRC31, LRRC32, LRRC34, LRRC36,LRRC37A, LRRC37A2, LRRC37A3, LRRC37B, LRRC38, LRRC39, LRRC3B, LRRC3C,LRRC4, LRRC40, LRRC41, LRRC42, LRRC43, LRRC45, LRRC46, LRRC47, LRRC49,LRRC4B, LRRC4C, LRRC52, LRRC53, LRRC55, LRRC56, LRRC57, LRRC58, LRRC59,LRRC6, LRRC61, LRRC63, LRRC66, LRRC69, LRRC7, LRRC70, LRRC71, LRRC72,LRRC73, LRRC74A, LRRC74B, LRRC75A, LRRC75B, LRRC8A, LRRC8B, LRRC8C,LRRC8D, LRRC8E, LRRC9, LRRCC1, LRRD1, LRRFIP1, LRRFIP2, LRRIQ1, LRRIQ3,LRRIQ4, LRRK1, LRRK2, LRRN1, LRRN2, LRRN3, LRRN4, LRRN4CL, LRRTM1,LRRTM2, LRRTM3, LRRTM4, LRSAM1, LRTM1, LRTM2, LRTOMT, LRWD1, LSAMP,LSG1, LSM1, LSM10, LSM11, LSM12, LSM14A, LSM14B, LSM2, LSM3, LSM4, LSM5,LSM6, LSM7, LSM8, LSMEM1, LSMEM2, LSP1, LSR, LSS, LST1, LTA, LTA4H, LTB,LTB4R, LTB4R2, LTBP1, LTBP2, LTBP3, LTBP4, LTBR, LTC4S, LTF, LTK, LTN1,LTV1, LUC7L, LUC7L2, LUC7L3, LUM, LURAP1, LURAP1L, LUZP1, LUZP2, LUZP4,LUZP6, LVRN, LXN, LY6D, LY6E, LY6G5B, LY6G5C, LY6G6C, LY6G6D, LY6G6E,LY6G6F, LY6H, LY6K, LY6L, LY75, LY75-CD302, LY86, LY9, LY96, LYAR, LYG1,LYG2, LYL1, LYN, LYNX1, LYPD1, LYPD2, LYPD3, LYPD4, LYPD5, LYPD6,LYPD6B, LYPD8, LYPLA1, LYPLA2, LYPLAL1, LYRM1, LYRM2, LYRM4, LYRM7,LYRM9, LYSMD1, LYSMD2, LYSMD3, LYSMD4, LYST, LYVE1, LYZ, LYZL1, LYZL2,LYZL4, LYZL6, LZIC, LZTFL1, LZTR1, LZTS1, LZTS2, LZTS3, M1AP, M6PR,MAATS1, MAB21L1, MAB21L2, MAB21L3, MACC1, MACF1, MACROD1, MACROD2,MAD1L1, MAD2L1, MAD2L1BP, MAD2L2, MADCAM1, MADD, MAEA, MAEL, MAF, MAF1,MAFA, MAFB, MAFF, MAFG, MAFK, MAG, MAGEA1, MAGEA10, MAGEA11, MAGEA12,MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA6, MAGEA8, MAGEA9, MAGEA9B,MAGEB1, MAGEB10, MAGEB16, MAGEB17, MAGEB18, MAGEB2, MAGEB3, MAGEB4,MAGEB5, MAGEB6, MAGEB6P1, MAGEC1, MAGEC2, MAGEC3, MAGED1, MAGED2,MAGED4, MAGED4B, MAGEE1, MAGEE2, MAGEF1, MAGEH1, MAGEL2, MAGI1, MAGI2,MAGI3, MAGIX, MAGOH, MAGOHB, MAGT1, MAIP1, MAJIN, MAK, MAK16, MAL, MAL2,MALL, MALRD1, MALSU1, MALT1, MAMDC2, MAMDC4, MAML1, MAML2, MAML3,MAMLD1, MAMSTR, MAN1A1, MAN1A2, MAN1B1, MAN1C1, MAN2A1, MAN2A2, MAN2B1,MAN2B2, MAN2C1, MANBA, MANBAL, MANEA, MANEAL, MANF, MANSC1, MANSC4,MAOA, MAOB, MAP10, MAP1A, MAP1B, MAP1LC3A, MAP1LC3B, MAP1LC3B2,MAP1LC3C, MAP1S, MAP2, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAP2K6,MAP2K7, MAP3K1, MAP3K10, MAP3K11, MAP3K12, MAP3K13, MAP3K14, MAP3K15,MAP3K19, MAP3K2, MAP3K20, MAP3K21, MAP3K3, MAP3K4, MAP3K5, MAP3K6,MAP3K7, MAP3K7CL, MAP3K8, MAP3K9, MAP4, MAP4K1, MAP4K2, MAP4K3, MAP4K4,MAP4K5, MAP6, MAP6D1, MAP7, MAP7D1, MAP7D2, MAP7D3, MAP9, MAPK1, MAPK10,MAPK11, MAPK12, MAPK13, MAPK14, MAPK15, MAPK1IP1L, MAPK3, MAPK4, MAPK6,MAPK7, MAPK8, MAPK8IP1, MAPK8IP2, MAPK8IP3, MAPK9, MAPKAP1, MAPKAPK2,MAPKAPK3, MAPKAPK5, MAPKBP1, MAPRE1, MAPRE2, MAPRE3, MAPT, MARC1, MARC2,MARCH1, MARCH10, MARCH11, MARCH2, MARCH3, MARCH4, MARCH5, MARCH6,MARCH7, MARCH8, MARCH9, MARCKS, MARCKSL1, MARCO, MARF1, MARK1, MARK2,MARK3, MARK4, MARS, MARS2, MARVELD1, MARVELD2, MARVELD3, MAS1, MAS1L,MASP1, MASP2, MAST1, MAST2, MAST3, MAST4, MASTL, MAT1A, MAT2A, MAT2B,MATK, MATN1, MATN2, MATN3, MATN4, MATR3, MAU2, MAVS, MAX, MAZ, MB,MB21D1, MB21D2, MBD1, MBD2, MBD3, MBD3L1, MBD3L2, MBD3L2B, MBD3L3,MBD3L4, MBD3L5, MBD4, MBD5, MBD6, MBIP, MBL2, MBLAC1, MBLAC2, MBNL1,MBNL2, MBNL3, MBOAT1, MBOAT2, MBOAT4, MBOAT7, MBP, MBTD1, MBTPS1,MBTPS2, MC1R, MC2R, MC3R, MC4R, MC5R, MCAM, MCAT, MCC, MCCC1, MCCC2,MCCD1, MCEE, MCEMP1, MCF2, MCF2L, MCF2L2, MCFD2, MCHR1, MCHR2, MCIDAS,MCL1, MCM10, MCM2, MCM3, MCM3AP, MCM4, MCM5, MCM6, MCM7, MCM8, MCM9,MCMBP, MCMDC2, MCOLN1, MCOLN2, MCOLN3, MCPH1, MCRIP1, MCRIP2, MCRS1,MCTP1, MCTP2, MCTS1, MCU, MCUB, MCUR1, MDC1, MDFI, MDFIC, MDFIC2, MDGA1,MDGA2, MDH1, MDH1B, MDH2, MDK, MDM1, MDM2, MDM4, MDN1, MDP1, MDS2, ME1,ME2, ME3, MEA1, MEAF6, MECOM, MECP2, MECR, MED1, MED10, MED11, MED12,MED12L, MED13, MED13L, MED14, MED14OS, MED15, MED16, MED17, MED18,MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED28,MED29, MED30, MED31, MED4, MED6, MED7, MED8, MED9, MEDAG, MEF2A, MEF2B,MEF2C, MEF2D, MEFV, MEGF10, MEGF11, MEGF6, MEGF8, MEGF9, MEI1, MEI4,MEIG1, MEIKIN, MEIOB, MEIOC, MEIS1, MEIS2, MEIS3, MELK, MELTF, MEMO1,MEN1, MEOX1, MEOX2, MEP1A, MEP1B, MEPCE, MEPE, MERTK, MESD, MESP1,MESP2, MEST, MET, METAP1, METAP1D, METAP2, METRN, METRNL, METTL1,METTL11B, METTL12, METTL13, METTL14, METTL15, METTL16, METTL17, METTL18,METTL21A, METTL21C, METTL22, METTL23, METTL24, METTL25, METTL26,METTL27, METTL2A, METTL2B, METTL3, METTL4, METTL5, METTL6, METTL7A,METTL7B, METTL8, METTL9, MEX3A, MEX3B, MEX3C, MEX3D, MFAP1, MFAP2,MFAP3, MFAP3L, MFAP4, MFAP5, MFF, MFGE8, MFHAS1, MFN1, MFN2, MFNG, MFRP,MFSD1, MFSD10, MFSD11, MFSD12, MFSD13A, MFSD14A, MFSD14B, MFSD14C,MFSD2A, MFSD2B, MFSD3, MFSD4A, MFSD4B, MFSD5, MFSD6, MFSD6L, MFSD7,MFSD8, MFSD9, MGA, MGAM, MGAM2, MGARP, MGAT1, MGAT2, MGAT3, MGAT4A,MGAT4B, MGAT4C, MGAT4D, MGAT5, MGAT5B, MGEA5, MGLL, MGME1, MGMT, MGP,MGRN1, MGST1, MGST2, MGST3, MIA, MIA3, MIA-RAB4B, MIB1, MIB2, MICA,MICAL1, MICAL2, MICAL3, MICALCL, MICALL1, MICALL2, MICB, MICU1, MICU2,MICU3, MID1, MID1IP1, MID2, MIDN, MIEF1, MIEF2, MIEN1, MIER1, MIER2,MIER3, MIF, MIF4GD, MIGA1, MIGA2, MIIP, MILR1, MINDY1, MINDY2, MINDY3,MINDY4, MINDY4B, MINK1, MINOS1, MINOS1-NBL1, MINPP1, MIOS, MIOX, MIP,MIPEP, MIPOL1, MIS12, MIS18A, MIS18BP1, MISP, MISP3, MITD1, MITF, MIXL1,MKI67, MKKS, MKL1, MKL2, MKLN1, MKNK1, MKNK2, MKRN1, MKRN2, MKRN2OS,MKRN3, MKS1, MKX, MLANA, MLC1, MLEC, MLF1, MLF2, MLH1, MLH3, MLIP, MLKL,MLLT1, MLLT10, MLLT11, MLLT3, MLLT6, MLN, MLNR, MLPH, MLST8, MLX, MLXIP,MLXIPL, MLYCD, MMAA, MMAB, MMACHC, MMADHC, MMD, MMD2, MME, MMEL1, MMGT1,MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMPP15, MMPP16, MMPP17, MMPP19,MMP2, MMP20, MMP21, MMP23B, MMP24, MMP24-AS1, MMP25, MMP26, MMP27,MMP28, MMP3, MMP7, MMP8, MMP9, MMRN1, MMRN2, MMS19, MMS22L, MN1, MNAT1,MND1, MNDA, MNS1, MNT, MNX1, MOAP1, MOB1A, MOB1B, MOB2, MOB3A, MOB3B,MOB3C, MOB4, MOBP, MOCOS, MOCS1, MOCS2, MOCS3, MOG, MOGAT1, MOGAT2,MOGAT3, MOGS, MOK, MON1A, MON1B, MON2, MORC1, MORC2, MORC3, MORC4,MORF4L1, MORF4L2, MORN1, MORN2, MORN3, MORN4, MORN5, MOS, MOSPD1,MOSPD2, MOSPD3, MOV10, MOV10L1, MOXD1, MPC1, MPC1L, MPC2, MPDU1, MPDZ,MPEG1, MPG, MPHOSPH10, MPHOSPH6, MPHOSPH8, MPHOSPH9, MPI, MPIG6B, MPL,MPLKIP, MPND, MPO, MPP1, MPP2, MPP3, MPP4, MPP5, MPP6, MPP7, MPPE1,MPPED1, MPPED2, MPRIP, MPST, MPV17, MPV17L, MPV17L2, MPZ, MPZL1, MPZL2,MPZL3, MR1, MRAP, MRAP2, MRAS, MRC1, MRC2, MRE11, MREG, MRFAP1,MRFAP1L1, MRGBP, MRGPRD, MRGPRE, MRGPRF, MRGPRG, MRGPRX1, MRGPRX2,MRGPRX3, MRGPRX4, MRI1, MRLN, MRM1, MRM2, MRM3, MRNIP, MRO, MROH1,MROH2A, MROH2B, MROH5, MROH6, MROH7, MROH7-TTC4, MROH8, MROH9, MRPL1,MRPL10, MRPL11, MRPL12, MRPL13, MRPL14, MRPL15, MRPL16, MRPL17, MRPL18,MRPL19, MRPL2, MRPL20, MRPL21, MRPL22, MRPL23, MRPL24, MRPL27, MRPL28,MRPL3, MRPL30, MRPL32, MRPL33, MRPL34, MRPL35, MRPL36, MRPL37, MRPL38,MRPL39, MRPL4, MRPL40, MRPL41, MRPL42, MRPL43, MRPL44, MRPL45, MRPL46,MRPL47, MRPL48, MRPL49, MRPL50, MRPL51, MRPL52, MRPL53, MRPL54, MRPL55,MRPL57, MRPL58, MRPL9, MRPS10, MRPS11, MRPS12, MRPS14, MRPS15, MRPS16,MRPS17, MRPS18A, MRPS18B, MRPS18C, MRPS2, MRPS21, MRPS22, MRPS23,MRPS24, MRPS25, MRPS26, MRPS27, MRPS28, MRPS30, MRPS31, MRPS33, MRPS34,MRPS35, MRPS36, MRPS5, MRPS6, MRPS7, MRPS9, MRRF, MRS2, MRTO4, MRVI1,MS4A1, MS4A10, MS4A12, MS4A13, MS4A14, MS4A15, MS4A2, MS4A3, MS4A4A,MS4A4E, MS4A5, MS4A6A, MS4A6E, MS4A7, MS4A8, MSANTD1, MSANTD2, MSANTD3,MSANTD3-TMEFF1, MSANTD4, MSC, MSGN1, MSH2, MSH3, MSH4, MSH5,MSH5-SAPCD1, MSH6, MSI1, MSI2, MSL1, MSL2, MSL3, MSLN, MSLNL, MSMB,MSMO1, MSMP, MSN, MSR1, MSRA, MSRB1, MSRB2, MSRB3, MSS51, MST1, MST1R,MSTN, MSTO1, MSX1, MSX2, MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1IL1,MT1M, MT1X, MT2A, MT3, MT4, MTA1, MTA2, MTA3, MTAP, MT-ATP6, MT-ATP8,MTBP, MTCH1, MTCH2, MTCL1, MT-CO1, MT-C02, MT-C03, MTCP1, MT-CYB, MTDH,MTERF1, MTERF2, MTERF3, MTERF4, MTF1, MTF2, MTFMT, MTFP1, MTFR1, MTFR1L,MTFR2, MTG1, MTG2, MTHFD1, MTHFD1L, MTHFD2, MTHFD2L, MTHFR, MTHFS,MTHFSD, MTIF2, MTIF3, MTM1, MTMR1, MTMR10, MTMR11, MTMR12, MTMR14,MTMR2, MTMR3, MTMR4, MTMR6, MTMR7, MTMR8, MTMR9, MT-ND1, MT-ND2, MT-ND3,MT-ND4, MT-ND4L, MT-ND5, MT-ND6, MTNR1A, MTNR1B, MTO1, MTOR, MTPAP,MTPN, MTR, MTRF1, MTRF1L, MTRNR2L1, MTRNR2L10, MTRNR2L11, MTRNR2L12,MTRNR2L13, MTRNR2L3, MTRNR2L4, MTRNR2L5, MTRNR2L6, MTRNR2L7, MTRNR2L8,MTRR, MTSS1, MTSS1L, MTTP, MTURN, MTUS1, MTUS2, MTX1, MTX2, MTX3, MUC1,MUC12, MUC13, MUC15, MUC16, MUC17, MUC2, MUC20, MUC21, MUC22, MUC3A,MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUCL1, MUL1, MUM1, MUM1L1, MUS81, MUSK,MUSTN1, MUT, MUTYH, MVB12A, MVB12B, MVD, MVK, MVP, MX1, MX2, MXD1, MXD3,MXD4, MXI1, MXRA5, MXRA7, MXRA8, MYADM, MYADML2, MYB, MYBBP1A, MYBL1,MYBL2, MYBPC1, MYBPC2, MYBPC3, MYBPH, MYBPHL, MYC, MYCBP, MYCBP2,MYCBPAP, MYCL, MYCN, MYCT1, MYD88, MYDGF, MYEF2, MYEOV, MYF5, MYF6,MYH1, MYH10, MYH11, MYH13, MYH14, MYH15, MYH2, MYH3, MYH4, MYH6, MYH7,MYH7B, MYH8, MYH9, MYL1, MYL10, MYL12A, MYL12B, MYL2, MYL3, MYL4, MYL5,MYL6, MYL6B, MYL7, MYL9, MYLIP, MYLK, MYLK2, MYLK3, MYLK4, MYLPF, MYMK,MYMX, MYNN, MYO10, MYO15A, MYO15B, MYO16, MYO18A, MYO18B, MYO19, MYO1A,MYO1B, MYO1C, MYO1D, MYO1E, MYO1F, MYO1G, MYO1H, MYO3A, MYO3B, MYO5A,MYO5B, MYO5C, MYO6, MYO7A, MYO7B, MYO9A, MYO9B, MYOC, MYOCD, MYOCOS,MYOD1, MYOF, MYOG, MYOM1, MYOM2, MYOM3, MYOT, MYOZ1, MYOZ2, MYOZ3, MYPN,MYPOP, MYRF, MYRFL, MYRIP, MYSM1, MYT1, MYT1L, MYZAP, MZB1, MZF1, MZT1,MZT2A, MZT2B, N4BP1, N4BP2, N4BP2L1, N4BP2L2, N4BP3, N6AMT1, NAA10,NAA11, NAA15, NAA16, NAA20, NAA25, NAA30, NAA35, NAA38, NAA40, NAA50,NAA60, NAAA, NAALAD2, NAALADL1, NAALADL2, NAB1, NAB2, NABP1, NABP2,NACA, NACA2, NACAD, NACC1, NACC2, NADK, NADK2, NADSYN1, NAE1, NAF1,NAGA, NAGK, NAGLU, NAGPA, NAGS, NAIF1, NAIP, NALCN, NAMPT, NANOG,NANOGNB, NANOGP8, NANOS1, NANOS2, NANOS3, NANP, NANS, NAP1L1, NAP1L2,NAP1L3, NAP1L4, NAP1L5, NAPA, NAPB, NAPEPLD, NAPG, NAPRT, NAPSA, NARF,NARFL, NARS, NARS2, NASP, NAT1, NAT10, NAT14, NAT16, NAT2, NAT6, NAT8,NAT8B, NAT8L, NAT9, NATD1, NAV1, NAV2, NAV3, NAXD, NAXE, NBAS, NBDY,NBEA, NBEAL1, NBEAL2, NBL1, NBN, NBPF1, NBPF10, NBPF11, NBPF12, NBPF14,NBPF15, NBPF19, NBPF20, NBPF26, NBPF3, NBPF4, NBPF6, NBPF9, NBR1, NCALD,NCAM1, NCAM2, NCAN, NCAPD2, NCAPD3, NCAPG, NCAPG2, NCAPH, NCAPH2, NCBP1,NCBP2, NCBP2-AS2, NCBP2L, NCBP3, NCCRP1, NCDN, NCEH1, NCF1, NCF2, NCF4,NCK1, NCK2, NCKAP1, NCKAP1L, NCKAP5, NCKAP5L, NCKIPSD, NCL, NCLN, NCMAP,NCOA1, NCOA2, NCOA3, NCOA4, NCOA5, NCOA6, NCOA7, NCOR1, NCOR2, NCR1,NCR2, NCR3, NCR3LG1, NCS1, NCSTN, NDC1, NDC80, NDE1, NDEL1, NDFIP1,NDFIP2, NDN, NDNF, NDOR1, NDP, NDRG1, NDRG2, NDRG3, NDRG4, NDST1, NDST2,NDST3, NDST4, NDUFA1, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFA2,NDUFA3, NDUFA4, NDUFA4L2, NDUFA5, NDUFA6, NDUFA7, NDUFA8, NDUFA9,NDUFAB1, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFAF7,NDUFAF8, NDUFB1, NDUFB10, NDUFB11, NDUFB2, NDUFB3, NDUFB4, NDUFB5,NDUFB6, NDUFB7, NDUFB8, NDUFB9, NDUFC1, NDUFC2, NDUFC2-KCTD14, NDUFS1,NDUFS2, NDUFS3, NDUFS4, NDUFS5, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2,NDUFV3, NEB, NEBL, NECAB1, NECAB2, NECAB3, NECAP1, NECAP2, NECTIN1,NECTIN2, NECTIN3, NECTIN4, NEDD1, NEDD4, NEDD4L, NEDD8, NEDD8-MDP1,NEDD9, NEFH, NEFL, NEFM, NEGR1, NEIL1, NEIL2, NEIL3, NEK1, NEK10, NEK11,NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK8, NEK9, NELFA, NELFB, NELFCD,NELFE, NELL1, NELL2, NEMF, NEMP1, NEMP2, NENF, NEO1, NEPRO, NES, NET1,NETO1, NETO2, NEU1, NEU2, NEU3, NEU4, NEURL1, NEURL1B, NEURL2, NEURL3,NEURL4, NEUROD1, NEUROD2, NEUROD4, NEUROD6, NEUROG1, NEUROG2, NEUROG3,NEXMIF, NEXN, NF1, NF2, NFAM1, NFASC, NFAT5, NFATC1, NFATC2, NFATC2IP,NFATC3, NFATC4, NFE2, NFE2L1, NFE2L2, NFE2L3, NFE4, NFIA, NFIB, NFIC,NFIL3, NFIX, NFKB1, NFKB2, NFKBIA, NFKBIB, NFKBID, NFKBIE, NFKBIL1,NFKBIZ, NFRKB, NFS1, NFU1, NFX1, NFXL1, NFYA, NFYB, NFYC, NGB, NGDN,NGEF, NGF, NGFR, NGLY1, NGRN, NHEJ1, NHLH1, NHLH2, NHLRC1, NHLRC2,NHLRC3, NHLRC4, NHP2, NHS, NHSL1, NHSL2, NICN1, NID1, NID2, NIF3L1,NIFK, NIM1K, NIN, NINJ1, NINJ2, NINL, NIP7, NIPA1, NIPA2, NIPAL1,NIPAL2, NIPAL3, NIPAL4, NIPBL, NIPSNAP1, NIPSNAP2, NIPSNAP3A, NIPSNAP3B,NISCH, NIT1, NIT2, NKAIN1, NKAIN2, NKAIN3, NKAIN4, NKAP, NKAPL, NKD1,NKD2, NKG7, NKIRAS1, NKIRAS2, NKPD1, NKRF, NKTR, NKX1-1, NKX1-2, NKX2-1,NKX2-2, NKX2-3, NKX2-4, NKX2-5, NKX2-6, NKX2-8, NKX3-1, NKX3-2, NKX6-1,NKX6-2, NKX6-3, NLE1, NLGN1, NLGN2, NLGN3, NLGN4X, NLGN4Y, NLK, NLN,NLRC3, NLRC4, NLRC5, NLRP1, NLRP10, NLRP11, NLRP12, NLRP13, NLRP14,NLRP2, NLRP2B, NLRP3, NLRP4, NLRP5, NLRP6, NLRP7, NLRP8, NLRP9, NLRX1,NMB, NMBR, NMD3, NME1, NME1-NME2, NME2, NME3, NME4, NME5, NME6, NME7,NME8, NME9, NMI, NMNAT1, NMNAT2, NMNAT3, NMRAL1, NMRK1, NMRK2, NMS,NMT1, NMT2, NMU, NMUR1, NMUR2, NNAT, NNMT, NNT, NOA1, NOB1, NOBOX,NOC2L, NOC3L, NOC4L, NOCT, NOD1, NOD2, NODAL, NOG, NOL10, NOL11, NOL12,NOL3, NOL4, NOL4L, NOL6, NOL7, NOL8, NOL9, NOLC1, NOM1, NOMO1, NOMO2,NOMO3, NONO, NOP10, NOP14, NOP16, NOP2, NOP53, NOP56, NOP58, NOP9, NOS1,NOS1AP, NOS2, NOS3, NOSIP, NOSTRIN, NOTCH1, NOTCH2, NOTCH2NL, NOTCH3,NOTCH4, NOTO, NOTUM, NOV, NOVA1, NOVA2, NOX1, NOX3, NOX4, NOX5, NOXA1,NOXO1, NOXRED1, NPAP1, NPAS1, NPAS2, NPAS3, NPAS4, NPAT, NPB, NPBWR1,NPBWR2, NPC1, NPC1L1, NPC2, NPDC1, NPEPL1, NPEPPS, NPFF, NPFFR1, NPFFR2,NPHP1, NPHP3, NPHP3-ACAD11, NPHP4, NPHS1, NPHS2, NPIPA1, NPIPA2, NPIPA3,NPIPA5, NPIPA7, NPIPA8, NPIPB11, NPIPB12, NPIPB13, NPIPB15, NPIPB2,NPIPB3, NPIPB4, NPIPB5, NPIPB6, NPIPB7, NPIPB8, NPIPB9, NPL, NPLOC4,NPM1, NPM2, NPM3, NPNT, NPPA, NPPB, NPPC, NPR1, NPR2, NPR3, NPRL2,NPRL3, NPS, NPSR1, NPTN, NPTX1, NPTX2, NPTXR, NPVF, NPW, NPY, NPY1R,NPY2R, NPY4R, NPY4R2, NPY5R, NQO1, NQO2, NR0B1, NR0B2, NR1D1, NR1D2,NR1H2, NR1H3, NR1H4, NR1I2, NR1I3, NR2C1, NR2C2, NR2C2AP, NR2E1, NR2E3,NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2,NR6A1, NRAP, NRARP, NRAS, NRBF2, NRBP1, NRBP2, NRCAM, NRDC, NRDE2, NREP,NRF1, NRG1, NRG2, NRG3, NRG4, NRGN, NRIP1, NRIP2, NRIP3, NRK, NRL, NRM,NRN1, NRN1L, NRP1, NRP2, NRROS, NRSN1, NRSN2, NRTN, NRXN1, NRXN2, NRXN3,NSA2, NSD1, NSD2, NSD3, NSDHL, NSF, NSFL1C, NSL1, NSMAF, NSMCE1, NSMCE2,NSMCE3, NSMCE4A, NSMF, NSRP1, NSUN2, NSUN3, NSUN4, NSUN5, NSUN6, NSUN7,NT5C, NT5C1A, NT5C1B, NT5C1B-RDH14, NT5C2, NT5C3A, NT5C3B, NT5DC1,NT5DC2, NT5DC3, NT5DC4, NT5E, NT5M, NTAN1, NTF3, NTF4, NTHL1, NTM,NTMT1, NTN1, NTN3, NTN4, NTN5, NTNG1, NTNG2, NTPCR, NTRK1, NTRK2, NTRK3,NTS, NTSR1, NTSR2, NUAK1, NUAK2, NUB1, NUBP1, NUBP2, NUBPL, NUCB1,NUCB2, NUCKS1, NUDC, NUDCD1, NUDCD2, NUDCD3, NUDT1, NUDT10, NUDT11,NUDT12, NUDT13, NUDT14, NUDT15, NUDT16, NUDT16L1, NUDT17, NUDT18,NUDT19, NUDT2, NUDT21, NUDT22, NUDT3, NUDT4, NUDT4P1, NUDT5, NUDT6,NUDT7, NUDT8, NUDT9, NUF2, NUFIP1, NUFIP2, NUGGC, NUMA1, NUMB, NUMBL,NUP107, NUP133, NUP153, NUP155, NUP160, NUP188, NUP205, NUP210, NUP210L,NUP214, NUP35, NUP37, NUP43, NUP50, NUP54, NUP58, NUP62, NUP62CL, NUP85,NUP88, NUP93, NUP98, NUPL2, NUPR1, NUPR2, NUS1, NUSAP1, NUTF2, NUTM1,NUTM2A, NUTM2B, NUTM2D, NUTM2E, NUTM2F, NUTM2G, NVL, NWD1, NWD2, NXF1,NXF2, NXF2B, NXF3, NXF5, NXN, NXNL1, NXNL2, NXPE1, NXPE2, NXPE3, NXPE4,NXPH1, NXPH2, NXPH3, NXPH4, NXT1, NXT2, NYAP1, NYAP2, NYNRIN, NYX, OAF,OARD1, OAS1, OAS2, OAS3, OASL, OAT, OAZ1, OAZ2, OAZ3, OBP2A, OBP2B,OBSCN, OBSCN-AS1, OBSL1, OC90, OCA2, OCEL1, OCIAD1, OCIAD2, OCLM, OCLN,OCM, OCM2, OCRL, OCSTAMP, ODAM, ODC1, ODF1, ODF2, ODF2L, ODF3, ODF3B,ODF3L1, ODF3L2, ODF4, OFCC1, OFD1, OGDH, OGDHL, OGFOD1, OGFOD2, OGFOD3,OGFR, OGFRL1, OGG1, OGN, OGT, OIP5, OIT3, OLA1, OLAH, OLFM1, OLFM2,OLFM3, OLFM4, OLFML1, OLFML2A, OLFML2B, OLFML3, OLIG1, OLIG2, OLIG3,OLR1, OMA1, OMD, OMG, OMP, ONECUT1, ONECUT2, ONECUT3, OOEP, OOSP2, OPA1,OPA3, OPALIN, OPCML, OPHN1, OPLAH, OPN1LW, OPN1MW, OPN1MW2, OPN1MW3,OPN1SW, OPN3, OPN4, OPN5, OPRD1, OPRK1, OPRL1, OPRM1, OPRPN, OPTC, OPTN,OR10A2, OR10A3, OR10A4, OR10A5, OR10A6, OR10A7, OR10AC1, OR10AD1,OR10AG1, OR10C1, OR10D3, OR10G2, OR10G3, OR10G4, OR10G6, OR10G7, OR10G8,OR10G9, OR10H1, OR10H2, OR10H3, OR10H4, OR10H5, OR10J1, OR10J3, OR10J4,OR10J5, OR10K1, OR10K2, OR10P1, OR10Q1, OR10R2, OR10S1, OR10T2, OR10V1,OR10W1, OR10X1, OR10Z1, OR11A1, OR11G2, OR11H1, OR11H12, OR11H2, OR11H4,OR11H6, OR11H7, OR11L1, OR12D1, OR12D2, OR12D3, OR13A1, OR13C2, OR13C3,OR13C4, OR13C5, OR13C7, OR13C8, OR13C9, OR13D1, OR13F1, OR13G1, OR13H1,OR13J1, OR14A16, OR14A2, OR14C36, OR14I1, OR14J1, OR14K1, OR1A1, OR1A2,OR1B1, OR1C1, OR1D2, OR1D5, OR1E1, OR1E2, OR1F1, OR1G1, OR1I1, OR1J1,OR1J2, OR1J4, OR1K1, OR1L1, OR1L3, OR1L4, OR1L6, OR1L8, OR1M1, OR1N1,OR1N2, OR1P1, OR1Q1, OR1S1, OR1S2, OR2A1, OR2A12, OR2A14, OR2A2, OR2A25,OR2A4, OR2A42, OR2A5, OR2A7, OR2AE1, OR2AG1, OR2AG2, OR2AJ1, OR2AK2,OR2AP1, OR2AT4, OR2B11, OR2B2, OR2B3, OR2B6, OR2C1, OR2C3, OR2D2, OR2D3,OR2F1, OR2F2, OR2G2, OR2G3, OR2G6, OR2H1, OR2H2, OR2J1, OR2J2, OR2J3,OR2K2, OR2L13, OR2L2, OR2L3, OR2L5, OR2L8, OR2M2, OR2M3, OR2M4, OR2M5,OR2M7, OR2S2, OR2T1, OR2T10, OR2T11, OR2T12, OR2T2, OR2T27, OR2T29,OR2T3, OR2T33, OR2T34, OR2T35, OR2T4, OR2T5, OR2T6, OR2T7, OR2T8, OR2V1,OR2V2, OR2W1, OR2W3, OR2Y1, OR2Z1, OR3A1, OR3A2, OR3A3, OR4A15, OR4A16,OR4A47, OR4A5, OR4A8, OR4B1, OR4C11, OR4C12, OR4C13, OR4C15, OR4C16,OR4C3, OR4C45, OR4C46, OR4C5, OR4C6, OR4D1, OR4D10, OR4D11, OR4D2,OR4D5, OR4D6, OR4D9, OR4E1, OR4E2, OR4F15, OR4F16, OR4F17, OR4F21,OR4F29, OR4F3, OR4F4, OR4F5, OR4F6, OR4K1, OR4K13, OR4K14, OR4K15,OR4K17, OR4K2, OR4K3, OR4K5, OR4L1, OR4M1, OR4M2, OR4N2, OR4N4, OR4N5,OR4P4, OR4Q2, OR4Q3, OR4S1, OR4S2, OR4X1, OR4X2, OR51A2, OR51A4, OR51A7,OR51B2, OR51B4, OR51B5, OR51B6, OR51D1, OR51E1, OR51E2, OR51F1, OR51F2,OR51G1, OR51G2, OR51H1, OR51I1, OR51I2, OR51J1, OR51L1, OR51M1, OR51Q1,OR51S1, OR51T1, OR51V1, OR52A1, OR52A5, OR52B2, OR52B4, OR52B6, OR52D1,OR52E2, OR52E4, OR52E5, OR52E6, OR52E8, OR52H1, OR52I1, OR52I2, OR52J3,OR52K1, OR52K2, OR52L1, OR52M1, OR52N1, OR52N2, OR52N4, OR52N5, OR52R1,OR52W1, OR52Z1, OR56A1, OR56A3, OR56A4, OR56A5, OR56B1, OR56B4, OR5A1,OR5A2, OR5AC1, OR5AC2, OR5AK2, OR5AN1, OR5AP2, OR5AR1, OR5AS1, OR5AU1,OR5B12, OR5B17, OR5B2, OR5B21, OR5B3, OR5C1, OR5D13, OR5D14, OR5D16,OR5D18, GR5F1, OR5G3, OR5H1, OR5H14, OR5H15, OR5H2, OR5H6, OR5H8, OR5I1,OR5J2, OR5K1, OR5K2, OR5K3, OR5K4, OR5L1, OR5L2, OR5M1, OR5M10, OR5M11,OR5M3, OR5M8, OR5M9, OR5P2, OR5P3, OR5R1, OR5T1, OR5T2, OR5T3, OR5V1,OR5W2, OR6A2, OR6B1, OR6B2, OR6B3, OR6C1, OR6C2, OR6C3, OR6C4, OR6C6,OR6C65, OR6C68, OR6C70, OR6C74, OR6C75, OR6C76, OR6F1, OR6J1, OR6K2,OR6K3, OR6K6, OR6M1, OR6N1, OR6N2, OR6P1, OR6Q1, OR6S1, OR6T1, OR6V1,OR6X1, OR6Y1, OR7A10, OR7A17, OR7A5, OR7C1, OR7C2, OR7D2, OR7D4, OR7E24,OR7G1, OR7G2, OR7G3, OR8A1, OR8B12, OR8B2, OR8B3, OR8B4, OR8B8, OR8D1,OR8D2, OR8D4, OR8G1, OR8G5, OR8H1, OR8H2, OR8H3, OR8I2, OR8J1, OR8J2,OR8J3, OR8K1, OR8K3, OR8K5, OR8S1, OR8U1, OR8U8, OR9A2, OR9A4, OR9G1,OR9G4, OR9G9, OR9H1P, OR9I1, OR9K2, OR9Q1, OR9Q2, ORAI1, ORAI2, ORAI3,ORAOV1, ORC1, ORC2, ORC3, ORC4, ORC5, ORC6, ORM1, ORM2, ORMDL1, ORMDL2,ORMDL3, OS9, OSBP, OSBP2, OSBPL10, OSBPL11, OSBPL1A, OSBPL2, OSBPL3,OSBPL5, OSBPL6, OSBPL7, OSBPL8, OSBPL9, OSCAR, OSCP1, OSER1, OSGEP,OSGEPL1, OSGIN1, OSGIN2, OSM, OSMR, OSR1, OSR2, OST4, OSTC, OSTF1,OSTM1, OSTN, OTC, OTOA, OTOF, OTOG, OTOGL, OTOL1, OTOP1, OTOP2, OTOP3,OTOR, OTOS, OTP, OTUB1, OTUB2, OTUD1, OTUD3, OTUD4, OTUD5, OTUD6A,OTUD6B, OTUD7A, OTUD7B, OTULIN, OTX1, OTX2, OVCA2, OVCH1, OVCH2, OVGP1,OVOL1, OVOL2, OVOL3, OXA1L, OXCT1, OXCT2, OXER1, OXGR1, OXLD1, OXNAD1,OXR1, OXSM, OXSR1, OXT, OXTR, P2RX1, P2RX2, P2RX3, P2RX4, P2RX5,P2RX5-TAX1BP3, P2RX6, P2RX7, P2RY1, P2RY10, P2RY11, P2RY12, P2RY13,P2RY14, P2RY2, P2RY4, P2RY6, P2RY8, P3H1, P3H2, P3H3, P3H4, P4HA1,P4HA2, P4HA3, P4HB, P4HTM, PA2G4, PAAF1, PABPC1, PABPC1L, PABPC1L2A,PABPC1L2B, PABPC3, PABPC4, PABPC4L, PABPC5, PABPN1, PABPN1L, PACRG,PACRGL, PACS1, PACS2, PACSIN1, PACSIN2, PACSIN3, PADI1, PADI2, PADI3,PADI4, PADI6, PAEP, PAF1, PAFAH1B1, PAFAH1B2, PAFAH1B3, PAFAH2, PAG1,PAGE1, PAGE2, PAGE2B, PAGE3, PAGE4, PAGE5, PAGR1, PAH, PAICS, PAIP1,PAIP2, PAIP2B, PAK1, PAK1IP1, PAK2, PAK3, PAK4, PAK5, PAK6, PALB2,PALD1, PALLD, PALM, PALM2, PALM2-AKAP2, PALM3, PALMD, PAM, PAM16, PAMR1,PAN2, PAN3, PANK1, PANK2, PANK3, PANK4, PANO1, PANX1, PANX2, PANX3,PAOX, PAPD4, PAPD5, PAPD7, PAPLN, PAPOLA, PAPOLB, PAPOLG, PAPPA, PAPPA2,PAPSS1, PAPSS2, PAQR3, PAQR4, PAQR5, PAQR6, PAQR7, PAQR8, PAQR9, PARD3,PARD3B, PARD6A, PARD6B, PARD6G, PARG, PARK7, PARL, PARM1, PARN, PARP1,PARP10, PARP11, PARP12, PARP14, PARP15, PARP16, PARP2, PARP3, PARP4,PARP6, PARP8, PARP9, PARPBP, PARS2, PARVA, PARVB, PARVG, PASD1, PASK,PATE1, PATE2, PATE3, PATE4, PATJ, PATL1, PATL2, PATZ1, PAWR, PAX1, PAX2,PAX3, PAX4, PAX5, PAX6, PAX7, PAX8, PAX9, PAXBP1, PAXIP1, PAXX, PBDC1,PBK, PBLD, PBOV1, PBRM1, PBX1, PBX2, PBX3, PBX4, PBXIP1, PC, PCBD1,PCBD2, PCBP1, PCBP2, PCBP3, PCBP4, PCCA, PCCB, PCDH1, PCDH10, PCDH11X,PCDH11Y, PCDH12, PCDH15, PCDH17, PCDH18, PCDH19, PCDH20, PCDH7, PCDH8,PCDH9, PCDHA1, PCDHA10, PCDHA11, PCDHA12, PCDHA13, PCDHA2, PCDHA3,PCDHA4, PCDHA5, PCDHA6, PCDHA7, PCDHA8, PCDHA9, PCDHAC1, PCDHAC2,PCDHB1, PCDHB10, PCDHB11, PCDHB12, PCDHB13, PCDHB14, PCDHB15, PCDHB16,PCDHB2, PCDHB3, PCDHB4, PCDHB5, PCDHB6, PCDHB7, PCDHB8, PCDHB9, PCDHGA1,PCDHGA10, PCDHGA11, PCDHGA12, PCDHGA2, PCDHGA3, PCDHGA4, PCDHGA5,PCDHGA6, PCDHGA7, PCDHGA8, PCDHGA9, PCDHGB1, PCDHGB2, PCDHGB3, PCDHGB4,PCDHGB5, PCDHGB6, PCDHGB7, PCDHGC3, PCDHGC4, PCDHGC5, PCED1A, PCED1B,PCF11, PCGF1, PCGF2, PCGF3, PCGF5, PCGF6, PCID2, PCIF1, PCK1, PCK2,PCLAF, PCLO, PCM1, PCMT1, PCMTD1, PCMTD2, PCNA, PCNP, PCNT, PCNX1,PCNX2, PCNX3, PCNX4, PCOLCE, PCOLCE2, PCOTH, PCP2, PCP4, PCP4L1, PCSK1,PCSK1N, PCSK2, PCSK4, PCSK5, PCSK6, PCSK7, PCSK9, PCTP, PCYOX1, PCYOX1L,PCYT1A, PCYT1B, PCYT2, PDAP1, PDC, PDCD1, PDCD10, PDCD11, PDCD1LG2,PDCD2, PDCD2L, PDCD4, PDCD5, PDCD6, PDCD6IP, PDCD7, PDCL, PDCL2, PDCL3,PDE10A, PDE11A, PDE12, PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE3B, PDE4A,PDE4B, PDE4C, PDE4D, PDE4DIP, PDE5A, PDE6A, PDE6B, PDE6C, PDE6D, PDE6G,PDE6H, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, PDF, PDGFA, PDGFB, PDGFC,PDGFD, PDGFRA, PDGFRB, PDGFRL, PDHA1, PDHA2, PDHB, PDHX, PDIA2, PDIA3,PDIA4, PDIA5, PDIA6, PDIK1L, PDILT, PDK1, PDK2, PDK3, PDK4, PDLIM1,PDLIM2, PDLIM3, PDLIM4, PDLIM5, PDLIM7, PDP1, PDP2, PDPK1, PDPN, PDPR,PDRG1, PDS5A, PDS5B, PDSS1, PDSS2, PDX1, PDXDC1, PDXK, PDXP, PDYN,PDZD11, PDZD2, PDZD3, PDZD4, PDZD7, PDZD8, PDZD9, PDZK1, PDZK1IP1,PDZRN3, PDZRN4, PEA15, PEAK1, PEAR1, PEBP1, PEBP4, PECAM1, PECR, PEF1,PEG10, PEG3, PELI1, PELI2, PELI3, PELO, PELP1, PEMT, PENK, PEPD, PER1,PER2, PER3, PERM1, PERP, PES1, PET100, PET117, PEX1, PEX10, PEX11A,PEX11B, PEX11G, PEX12, PEX13, PEX14, PEX16, PEX19, PEX2, PEX26, PEX3,PEX5, PEX5L, PEX6, PEX7, PF4, PF4V1, PFAS, PFDN1, PFDN2, PFDN4, PFDN5,PFDN6, PFKFB1, PFKFB2, PFKFB3, PFKFB4, PFKL, PFKM, PFKP, PFN1, PFN2,PFN3, PFN4, PGA3, PGA4, PGA5, PGAM1, PGAM2, PGAM4, PGAM5, PGAP1, PGAP2,PGAP3, PGBD1, PGBD2, PGBD4, PGBD5, PGC, PGD, PGF, PGGHG, PGGTIB, PGK1,PGK2, PGLS, PGLYRP1, PGLYRP2, PGLYRP3, PGLYRP4, PGM1, PGM2, PGM2L1,PGM3, PGM5, PGP, PGPEP1, PGPEP1L, PGR, PGRMC1, PGRMC2, PGS1, PHACTR1,PHACTR2, PHACTR3, PHACTR4, PHAX, PHB, PHB2, PHC1, PHC2, PHC3, PHEX,PHF1, PHF10, PHF11, PHF12, PHF13, PHF14, PHF19, PHF2, PHF20, PHF20L1,PHF21A, PHF21B, PHF23, PHF24, PHF3, PHF5A, PHF6, PHF7, PHF8, PHGDH,PHGR1, PHIP, PHKA1, PHKA2, PHKB, PHKG1, PHKG2, PHLDA1, PHLDA2, PHLDA3,PHLDB1, PHLDB2, PHLDB3, PHLPP1, PHLPP2, PHOSPHO1, PHOSPHO2, PHOX2A,PHOX2B, PHPT1, PHRF1, PHTF1, PHTF2, PHYH, PHYHD1, PHYHIP, PHYHIPL,PHYKPL, PI15, PI16, PI3, PI4K2A, PI4K2B, PI4KA, PI4KB, PIANP, PIAS1,PIAS2, PIAS3, PIAS4, PIBF1, PICALM, PICK1, PID1, PIDD1, PIEZO1, PIEZO2,PIF1, PIFO, PIGA, PIGB, PIGBOS1, PIGC, PIGF, PIGG, PIGH, PIGK, PIGL,PIGM, PIGN, PIGO, PIGP, PIGQ, PIGR, PIGS, PIGT, PIGU, PIGV, PIGW, PIGX,PIGY, PIGZ, PIH1D1, PIH1D2, PIH1D3, PIK3AP1, PIK3C2A, PIK3C2B, PIK3C2G,PIK3C3, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3,PIK3R4, PIK3R5, PIK3R6, PIKFYVE, PILRA, PILRB, PIM1, PIM2, PIM3, PIMREG,PIN1, PIN4, PINK1, PINLYP, PINX1, PIP, PIP4K2A, PIP4K2B, PIP4K2C,PIP5K1A, PIP5K1B, PIP5K1C, PIP5KL1, PIPOX, PIR, PIRT, PISD, PITHD1,PITPNA, PITPNB, PITPNC1, PITPNM1, PITPNM2, PITPNM3, PITRM1, PITX1,PITX2, PITX3, PIWIL1, PIWIL2, PIWIL3, PIWIL4, PJA1, PJA2, PKD1, PKD1L1,PKD1L2, PKD1L3, PKD2, PKD2L1, PKD2L2, PKDCC, PKDREJ, PKHD1, PKHDIL1,PKIA, PKIB, PKIG, PKLR, PKM, PKMYT1, PKN1, PKN2, PKN3, PKNOX1, PKNOX2,PKP1, PKP2, PKP3, PKP4, PLA1A, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15,PLA2G16, PLA2G1B, PLA2G2A, PLA2G2C, PLA2G2D, PLA2G2E, PLA2G2F, PLA2G3,PLA2G4A, PLA2G4B, PLA2G4C, PLA2G4D, PLA2G4E, PLA2G4F, PLA2G5, PLA2G6,PLA2G7, PLA2R1, PLAA, PLAC1, PLAC4, PLAC8, PLAC8L1, PLAC9, PLAG1,PLAGL1, PLAGL2, PLAT, PLAU, PLAUR, PLB1, PLBD1, PLBD2, PLCB1, PLCB2,PLCB3, PLCB4, PLCD1, PLCD3, PLCD4, PLCE1, PLCG1, PLCG2, PLCH1, PLCH2,PLCL1, PLCL2, PLCXD1, PLCXD2, PLCXD3, PLCZ1, PLD1, PLD2, PLD3, PLD4,PLD5, PLD6, PLEC, PLEK, PLEK2, PLEKHA1, PLEKHA2, PLEKHA3, PLEKHA4,PLEKHA5, PLEKHA6, PLEKHA7, PLEKHA8, PLEKHB1, PLEKHB2, PLEKHD1, PLEKHF1,PLEKHF2, PLEKHG1, PLEKHG2, PLEKHG3, PLEKHG4, PLEKHG4B, PLEKHG5, PLEKHG6,PLEKHG7, PLEKHH1, PLEKHH2, PLEKHH3, PLEKHJ1, PLEKHM1, PLEKHM2, PLEKHM3,PLEKHN1, PLEKHO1, PLEKHO2, PLEKHS1, PLET1, PLG, PLGLB1, PLGLB2, PLGRKT,PLIN1, PLIN2, PLIN3, PLIN4, PLIN5, PLK1, PLK2, PLK3, PLK4, PLK5, PLLP,PLN, PLOD1, PLOD2, PLOD3, PLP1, PLP2, PLPBP, PLPP1, PLPP2, PLPP3, PLPP4,PLPP5, PLPP6, PLPP7, PLPPR1, PLPPR2, PLPPR3, PLPPR4, PLPPR5, PLRG1,PLS1, PLS3, PLSCR1, PLSCR2, PLSCR3, PLSCR4, PLSCR5, PLTP, PLVAP, PLXDC1,PLXDC2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, PLXNB1, PLXNB2, PLXNB3, PLXNC1,PLXND1, PM20D1, PM20D2, PMAIP1, PMCH, PMEL, PMEPA1, PMF1, PMF1-BGLAP,PMFBP1, PML, PMM1, PMM2, PMP2, PMP22, PMPCA, PMPCB, PMS1, PMS2, PMVK,PNCK, PNISR, PNKD, PNKP, PNLDC1, PNLIP, PNLIPRP1, PNLIPRP2, PNLIPRP3,PNMA1, PNMA2, PNMA3, PNMA5, PNMA6A, PNMA6E, PNMA6F, PNMA8A, PNMA8B,PNMA8C, PNMT, PNN, PNO1, PNOC, PNP, PNPLA1, PNPLA2, PNPLA3, PNPLA4,PNPLA5, PNPLA6, PNPLA7, PNPLA8, PNPO, PNPT1, PNRC1, PNRC2, POC1A, POC1B,POC1B-GALNT4, POC5, PODN, PODNL1, PODXL, PODXL2, POF1B, POFUT1, POFUT2,POGK, POGLUT1, POGZ, POLA1, POLA2, POLB, POLD1, POLD2, POLD3, POLD4,POLDIP2, POLDIP3, POLE, POLE2, POLE3, POLE4, POLG, POLG2, POLH, POLI,POLK, POLL, POLM, POLN, POLQ, POLR1A, POLR1B, POLR1C, POLR1D, POLR1E,POLR2A, POLR2B, POLR2C, POLR2D, POLR2E, POLR2F, POLR2G, POLR2H, POLR2I,POLR2J, POLR2J2, POLR2J3, POLR2K, POLR2L, POLR2M, POLR3A, POLR3B,POLR3C, POLR3D, POLR3E, POLR3F, POLR3G, POLR3GL, POLR3H, POLR3K, POLRMT,POM121, POM121C, POM121L12, POM121L2, POMC, POMGNT1, POMGNT2, POMK,POMP, POMT1, POMT2, POMZP3, PON1, PON2, PON3, POP1, POP4, POP5, POP7,POPDC2, POPDC3, POR, PORCN, POSTN, POT1, POTEA, POTEB, POTEB2, POTEB3,POTEC, POTED, POTEE, POTEF, POTEG, POTEH, POTEI, POTEJ, POTEM, POU1F1,POU2AF1, POU2F1, POU2F2, POU2F3, POU3F1, POU3F2, POU3F3, POU3F4, POU4F1,POU4F2, POU4F3, POU5F1, POU5F1B, POU5F2, POU6F1, POU6F2, PP2D1, PPA1,PPA2, PPAN, PPAN-P2RY11, PPARA, PPARD, PPARG, PPARGC1A, PPARGC1B, PPAT,PPBP, PPCDC, PPCS, PPDPF, PPEF1, PPEF2, PPFIA1, PPFIA2, PPFIA3, PPFIA4,PPFIBP1, PPFIBP2, PPHLN1, PPIA, PPIAL4A, PPIAL4C, PPIAL4D, PPIAL4E,PPIAL4F, PPIAL4G, PPIB, PPIC, PPID, PPIE, PPIF, PPIG, PPIH, PPIL1,PPIL2, PPIL3, PPIL4, PPIL6, PPIP5K1, PPIP5K2, PPL, PPM1A, PPM1B, PPM1D,PPM1E, PPM1F, PPM1G, PPM1H, PPM1J, PPM1K, PPM1L, PPM1M, PPM1N, PPME1,PPOX, PPP1CA, PPP1CB, PPP1CC, PPP1R10, PPP1R11, PPP1R12A, PPP1R12B,PPP1R12C, PPP1R13B, PPP1R13L, PPP1R14A, PPP1R14B, PPP1R14C, PPP1R14D,PPP1R15A, PPP1R15B, PPP1R16A, PPP1R16B, PPP1R17, PPP1R18, PPP1R1A,PPP1R1B, PPP1R1C, PPP1R2, PPP1R21, PPP1R26, PPP1R27, PPP1R2P3, PPP1R2P9,PPP1R32, PPP1R35, PPP1R36, PPP1R37, PPP1R3A, PPP1R3B, PPP1R3C, PPP1R3D,PPP1R3E, PPP1R3F, PPP1R3G, PPP1R42, PPP1R7, PPP1R8, PPP1R9A, PPP1R9B,PPP2CA, PPP2CB, PPP2R1A, PPP2R1B, PPP2R2A, PPP2R2B, PPP2R2C, PPP2R2D,PPP2R3A, PPP2R3B, PPP2R3C, PPP2R5A, PPP2R5B, PPP2R5C, PPP2R5D, PPP2R5E,PPP3CA, PPP3CB, PPP3CC, PPP3R1, PPP3R2, PPP4C, PPP4R1, PPP4R2, PPP4R3A,PPP4R3B, PPP4R3CP, PPP4R4, PPP5C, PPP5D1, PPP6C, PPP6R1, PPP6R2, PPP6R3,PPRC1, PPT1, PPT2, PPT2-EGFL8, PPTC7, PPWD1, PPY, PQBP1, PQLC1, PQLC2,PQLC2L, PQLC3, PRAC1, PRAC2, PRADC1, PRAF2, PRAG1, PRAM1, PRAME,PRAMEF1, PRAMEF10, PRAMEF11, PRAMEF12, PRAMEF13, PRAMEF14, PRAMEF15,PRAMEF17, PRAMEF18, PRAMEF19, PRAMEF2, PRAMEF20, PRAMEF25, PRAMEF26,PRAMEF27, PRAMEF33, PRAMEF4, PRAMEF5, PRAMEF6, PRAMEF7, PRAMEF8,PRAMEF9, PRAP1, PRB1, PRB2, PRB3, PRB4, PRC1, PRCC, PRCD, PRCP, PRDM1,PRDM10, PRDM11, PRDM12, PRDM13, PRDM14, PRDM15, PRDM16, PRDM2, PRDM4,PRDM5, PRDM6, PRDM7, PRDM8, PRDM9, PRDX1, PRDX2, PRDX3, PRDX4, PRDX5,PRDX6, PREB, PRELID1, PRELID2, PRELID3A, PRELID3B, PRELP, PREP, PREPL,PREX1, PREX2, PRF1, PRG2, PRG3, PRG4, PRH1, PRH2, PRICKLE1, PRICKLE2,PRICKLE3, PRICKLE4, PRIM1, PRIM2, PRIMA1, PRIMPOL, PRKAA1, PRKAA2,PRKAB1, PRKAB2, PRKACA, PRKACB, PRKACG, PRKAG1, PRKAG2, PRKAG3, PRKAR1A,PRKAR1B, PRKAR2A, PRKAR2B, PRKCA, PRKCB, PRKCD, PRKCE, PRKCG, PRKCH,PRKCI, PRKCQ, PRKCSH, PRKCZ, PRKD1, PRKD2, PRKD3, PRKDC, PRKG1, PRKG2,PRKN, PRKRA, PRKRIP1, PRKX, PRL, PRLH, PRLHR, PRLR, PRM1, PRM2, PRM3,PRMT1, PRMT2, PRMT3, PRMT5, PRMT6, PRMT7, PRMT8, PRMT9, PRND, PRNP,PRNT, PROB1, PROC, PROCA1, PROCR, PRODH, PRODH2, PROK1, PROK2, PROKR1,PROKR2, PROM1, PROM2, PROP1, PRORY, PROS1, PROSER1, PROSER2, PROSER3,PROX1, PROX2, PROZ, PRPF18, PRPF19, PRPF3, PRPF31, PRPF38A, PRPF38B,PRPF39, PRPF4, PRPF40A, PRPF40B, PRPF4B, PRPF6, PRPF8, PRPH, PRPH2,PRPS1, PRPS1L1, PRPS2, PRPSAP1, PRPSAP2, PRR11, PRR12, PRR13, PRR14,PRR14L, PRR15, PRR15L, PRR16, PRR18, PRR19, PRR20A, PRR20B, PRR20C,PRR20D, PRR20E, PRR21, PRR22, PRR23A, PRR23B, PRR23C, PRR23D1, PRR23D2,PRR25, PRR26, PRR27, PRR29, PRR3, PRR30, PRR32, PRR34, PRR35, PRR36,PRR4, PRR5, PRR5-ARHGAP8, PRR5L, PRR7, PRR9, PRRC1, PRRC2A, PRRC2B,PRRC2C, PRRG1, PRRG2, PRRG3, PRRG4, PRRT1, PRRT2, PRRT3, PRRT4, PRRX1,PRRX2, PRSS1, PRSS12, PRSS16, PRSS2, PRSS21, PRSS22, PRSS23, PRSS27,PRSS3, PRSS33, PRSS35, PRSS36, PRSS37, PRSS38, PRSS41, PRSS42, PRSS45,PRSS46, PRSS48, PRSS50, PRSS51, PRSS53, PRSS54, PRSS55, PRSS56, PRSS57,PRSS58, PRSS8, PRTFDC1, PRTG, PRTN3, PRUNE1, PRUNE2, PRX, PRY, PRY2,PSAP, PSAPL1, PSAT1, PSCA, PSD, PSD2, PSD3, PSD4, PSEN1, PSEN2, PSENEN,PSG1, PSG11, PSG2, PSG3, PSG4, PSG5, PSG6, PSG7, PSG8, PSG9, PSIP1,PSKH1, PSKH2, PSMA1, PSMA2, PSMA3, PSMA4, PSMA5, PSMA6, PSMA7, PSMA8,PSMB1, PSMB10, PSMB11, PSMB2, PSMB3, PSMB4, PSMB5, PSMB6, PSMB7, PSMB8,PSMB9, PSMC1, PSMC2, PSMC3, PSMC3IP, PSMC4, PSMC5, PSMC6, PSMD1, PSMD10,PSMD11, PSMD12, PSMD13, PSMD14, PSMD2, PSMD3, PSMD4, PSMD5, PSMD6,PSMD7, PSMD8, PSMD9, PSME1, PSME2, PSME3, PSME4, PSMF1, PSMG1, PSMG2,PSMG3, PSMG4, PSORS1C1, PSORS1C2, PSPC1, PSPH, PSPN, PSRC1, PSTK,PSTPIP1, PSTPIP2, PTAFR, PTAR1, PTBP1, PTBP2, PTBP3, PTCD1, PTCD2,PTCD3, PTCH1, PTCH2, PTCHD1, PTCHD3, PTCHD4, PTCRA, PTDSS1, PTDSS2,PTEN, PTER, PTF1A, PTGDR, PTGDR2, PTGDS, PTGER1, PTGER2, PTGER3, PTGER4,PTGES, PTGES2, PTGES3, PTGES3L, PTGES3L-AARSD1, PTGFR, PTGFRN, PTGIR,PTGIS, PTGR1, PTGR2, PTGS1, PTGS2, PTH, PTH1R, PTH2, PTH2R, PTHLH, PTK2,PTK2B, PTK6, PTK7, PTMA, PTMS, PTN, PTOV1, PTP4A1, PTP4A2, PTP4A3, PTPA,PTPDC1, PTPMT1, PTPN1, PTPN11, PTPN12, PTPN13, PTPN14, PTPN18, PTPN2,PTPN20, PTPN21, PTPN22, PTPN23, PTPN3, PTPN4, PTPN5, PTPN6, PTPN7,PTPN9, PTPRA, PTPRB, PTPRC, PTPRCAP, PTPRD, PTPRE, PTPRF, PTPRG, PTPRH,PTPRJ, PTPRK, PTPRM, PTPRN, PTPRN2, PTPRO, PTPRQ, PTPRR, PTPRS, PTPRT,PTPRU, PTPRZ1, PTRH1, PTRH2, PTRHD1, PTS, PTTG1, PTTG1IP, PTTG2, PTX3,PTX4, PUDP, PUF60, PUM1, PUM2, PUM3, PURA, PURB, PURG, PUS1, PUS10,PUS3, PUS7, PUS7L, PUSL1, PVALB, PVR, PVRIG, PWP1, PWP2, PWWP2A, PWWP2B,PXDC1, PXDN, PXDNL, PXK, PXMP2, PXMP4, PXN, PXT1, PXYLP1, PYCARD, PYCR1,PYCR2, PYCR3, PYDC1, PYDC2, PYGB, PYGL, PYGM, PYGO1, PYGO2, PYHIN1,PYM1, PYROXD1, PYROXD2, PYURF, PYY, PZP, QARS, QDPR, QKI, QPCT, QPCTL,QPRT, QRFP, QRFPR, QRICH1, QRICH2, QRSL1, QSER1, QSOX1, QSOX2, QTRT1,QTRT2, R3HCC1, R3HCC1L, R3HDM1, R3HDM2, R3HDM4, R3HDML, RAB10, RAB11A,RAB11B, RAB11FIP1, RAB11FIP2, RAB11FIP3, RAB11FIP4, RAB11FIP5, RAB12,RAB13, RAB14, RAB15, RAB17, RAB18, RAB19, RAB1A, RAB1B, RAB20, RAB21,RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB29, RAB2A,RAB2B, RAB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37,RAB38, RAB39A, RAB39B, RAB3A, RAB3B, RAB3C, RAB3D, RAB3GAP1, RAB3GAP2,RAB3IL1, RAB3IP, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42, RAB43,RAB44, RAB4A, RAB4B, RAB4B-EGLN2, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B,RAB6C, RAB7A, RAB7B, RAB8A, RAB8B, RAB9A, RAB9B, RABAC1, RABEP1, RABEP2,RABEPK, RABGAP1, RABGAP1L, RABGEF1, RABGGTA, RABGGTB, RABIF, RABL2A,RABL2B, RABL3, RABL6, RAC1, RAC2, RAC3, RACGAP1, RACK1, RAD1, RAD17,RAD18, RAD21, RAD21L1, RAD23A, RAD23B, RAD50, RAD51, RAD51AP1, RAD51AP2,RAD51B, RAD51C, RAD51D, RAD52, RAD54B, RAD54L, RAD54L2, RAD9A, RAD9B,RADTL, RAE1, RAETIE, RAETIG, RAET1L, RAF1, RAG1, RAG2, RAI1, RAI14,RAI2, RALA, RALB, RALBP1, RALGAPA1, RALGAPA2, RALGAPB, RALGDS, RALGPS1,RALGPS2, RALY, RALYL, RAMP1, RAMP2, RAMP3, RAN, RANBP1, RANBP10,RANBP17, RANBP2, RANBP3, RANBP3L, RANBP6, RANBP9, RANGAP1, RANGRF,RAP1A, RAP1B, RAP1GAP, RAP1GAP2, RAP1GDS1, RAP2A, RAP2B, RAP2C, RAPGEF1,RAPGEF2, RAPGEF3, RAPGEF4, RAPGEF5, RAPGEF6, RAPGEFL1, RAPH1, RAPSN,RARA, RARB, RARG, RARRES1, RARRES2, RARRES3, RARS, RARS2, RASA1, RASA2,RASA3, RASA4, RASA4B, RASAL1, RASAL2, RASAL3, RASD1, RASD2, RASEF,RASGEF1A, RASGEF1B, RASGEF1C, RASGRF1, RASGRF2, RASGRP1, RASGRP2,RASGRP3, RASGRP4, RASIP1, RASL10A, RASL10B, RASL11A, RASL11B, RASL12,RASSF1, RASSF10, RASSF2, RASSF3, RASSF4, RASSF5, RASSF6, RASSF7, RASSF8,RASSF9, RAVER1, RAVER2, RAX, RAX2, RB1, RB1CC1, RBAK, RBAK-RBAKDN,RBBP4, RBBP5, RBBP6, RBBP7, RBBP8, RBBP8NL, RBBP9, RBCK1, RBFA, RBFOX1,RBFOX2, RBFOX3, RBKS, RBL1, RBL2, RBM10, RBM11, RBM12, RBM12B, RBM14,RBM14-RBM4, RBM15, RBM15B, RBM17, RBM18, RBM19, RBM20, RBM22, RBM23,RBM24, RBM25, RBM26, RBM27, RBM28, RBM3, RBM33, RBM34, RBM38, RBM39,RBM4, RBM41, RBM42, RBM43, RBM44, RBM45, RBM46, RBM47, RBM48, RBM4B,RBM5, RBM6, RBM7, RBM8A, RBMS1, RBMS2, RBMS3, RBMX, RBMX2, RBMXL1,RBMXL2, RBMXL3, RBMY1A1, RBMY1B, RBMY1D, RBMY1E, RBMY1F, RBMY1J, RBP1,RBP2, RBP3, RBP4, RBP5, RBP7, RBPJ, RBPJL, RBPMS, RBPMS2, RBSN, RBX1,RC3H1, RC3H2, RCAN1, RCAN2, RCAN3, RCBTB1, RCBTB2, RCC1, RCC1L, RCC2,RCCD1, RCE1, RCHY1, RCL1, RCN1, RCN2, RCN3, RCOR1, RCOR2, RCOR3, RCSD1,RCVRN, RD3, RD3L, RDH10, RDH11, RDH12, RDH13, RDH14, RDH16, RDH5, RDH8,RDM1, RDX, REC114, REC8, RECK, RECQL, RECQL4, RECQL5, REEP1, REEP2,REEP3, REEP4, REEP5, REEP6, REG1A, REG1B, REG3A, REG3G, REG4, REL, RELA,RELB, RELL1, RELL2, RELN, RELT, REM1, REM2, REN, RENBP, REP15, REPIN1,REPS1, REPS2, RER1, RERE, RERG, RERGL, RESP18, REST, RET, RETN, RETNLB,RETREG1, RETREG2, RETREG3, RETSAT, REV1, REV3L, REXO1, REXO2, REXO4,REXO5, RFC1, RFC2, RFC3, RFC4, RFC5, RFESD, RFFL, RFK, RFLNA, RFLNB,RFNG, RFPL1, RFPL2, RFPL3, RFPL3S, RFPL4A, RFPL4AL1, RFPL4B, RFT1,RFTN1, RFTN2, RFWD2, RFWD3, RFX1, RFX2, RFX3, RFX4, RFX5, RFX6, RFX7,RFX8, RFXANK, RFXAP, RGCC, RGL1, RGL2, RGL3, RGL4, RGMA, RGMB, RGN,RGP1, RGPD1, RGPD2, RGPD3, RGPD4, RGPD5, RGPD6, RGPD8, RGR, RGS1, RGS10,RGS11, RGS12, RGS13, RGS14, RGS16, RGS17, RGS18, RGS19, RGS2, RGS20,RGS21, RGS22, RGS3, RGS4, RGS5, RGS6, RGS7, RGS7BP, RGS8, RGS9, RGS9BP,RGSL1, RHAG, RHBDD1, RHBDD2, RHBDD3, RHBDF1, RHBDF2, RHBDL1, RHBDL2,RHBDL3, RHBG, RHCE, RHCG, RHD, RHEB, RHEBL1, RHNO1, RHO, RHOA, RHOB,RHOBTB1, RHOBTB2, RHOBTB3, RHOC, RHOD, RHOF, RHOG, RHOH, RHOJ, RHOQ,RHOT1, RHOT2, RHOU, RHOV, RHOXF1, RHOXF2, RHOXF2B, RHPN1, RHPN2, RIBC1,RIBC2, RIC1, RIC3, RIC8A, RIC8B, RICTOR, RIDA, RIF1, RIIAD1, RILP,RILPL1, RILPL2, RIMBP2, RIMBP3, RIMBP3B, RIMBP3C, RIMKLA, RIMKLB, RIMS1,RIMS2, RIMS3, RIMS4, RIN1, RIN2, RIN3, RING1, RINL, RINT1, RIOK1, RIOK2,RIOK3, RIOX1, RIOX2, RIPK1, RIPK2, RIPK3, RIPK4, RIPOR1, RIPOR2, RIPOR3,RIPPLY1, RIPPLY2, RIPPLY3, RIT1, RIT2, RITA1, RLBP1, RLF, RLIM, RLN1,RLN2, RLN3, RMDN1, RMDN2, RMDN3, RMI1, RMI2, RMND1, RMND5A, RMND5B,RNASE1, RNASE10, RNASE11, RNASE12, RNASE13, RNASE2, RNASE3, RNASE4,RNASE6, RNASE7, RNASE8, RNASE9, RNASEH1, RNASEH2A, RNASEH2B, RNASEH2C,RNASEK, RNASEK-C17orf49, RNASEL, RNASET2, RND1, RND2, RND3, RNF10,RNF103, RNF103-CHMP3, RNF11, RNF111, RNF112, RNF113A, RNF113B, RNF114,RNF115, RNF121, RNF122, RNF123, RNF125, RNF126, RNF128, RNF13, RNF130,RNF133, RNF135, RNF138, RNF139, RNF14, RNF141, RNF144A, RNF144B, RNF145,RNF146, RNF148, RNF149, RNF150, RNF151, RNF152, RNF157, RNF165, RNF166,RNF167, RNF168, RNF169, RNF17, RNF170, RNF175, RNF180, RNF181, RNF182,RNF183, RNF185, RNF186, RNF187, RNF19A, RNF19B, RNF2, RNF20, RNF207,RNF208, RNF212, RNF212B, RNF213, RNF214, RNF215, RNF216, RNF217, RNF219,RNF220, RNF222, RNF223, RNF224, RNF225, RNF24, RNF25, RNF26, RNF31,RNF32, RNF34, RNF38, RNF39, RNF4, RNF40, RNF41, RNF43, RNF44, RNF5,RNF6, RNF7, RNF8, RNFT1, RNFT2, RNGTT, RNH1, RNLS, RNMT, RNPC3, RNPEP,RNPEPL1, RNPS1, ROBO1, ROBO2, ROBO3, ROBO4, ROCK1, ROCK2, ROGDI, ROM1,ROMO1, ROPN1, ROPN1B, ROPN1L, ROR1, ROR2, RORA, RORB, RORC, ROS1, RP1,RP1L1, RP2, RP9, RPA1, RPA2, RPA3, RPA4, RPAIN, RPAP1, RPAP2, RPAP3,RPE, RPE65, RPEL1, RPF1, RPF2, RPGR, RPGRIP1, RPGRIP1L, RPH3A, RPH3AL,RPIA, RPL10, RPL10A, RPL10L, RPL11, RPL12, RPL13, RPL13A, RPL14, RPL15,RPL17, RPL17-C18orf32, RPL18, RPL18A, RPL19, RPL21, RPL22, RPL22L1,RPL23, RPL23A, RPL24, RPL26, RPL26L1, RPL27, RPL27A, RPL28, RPL29, RPL3,RPL30, RPL31, RPL32, RPL34, RPL35, RPL35A, RPL36, RPL36A,RPL36A-HNRNPH2, RPL36AL, RPL37, RPL37A, RPL38, RPL39, RPL39L, RPL3L,RPL4, RPL41, RPL5, RPL6, RPL7, RPL7A, RPL7L1, RPL8, RPL9, RPLP0, RPLP1,RPLP2, RPN1, RPN2, RPP14, RPP21, RPP25, RPP25L, RPP30, RPP38, RPP40,RPRD1A, RPRD1B, RPRD2, RPRM, RPRML, RPS10, RPS10-NUDT3, RPS11, RPS12,RPS13, RPS14, RPS15, RPS15A, RPS16, RPS17, RPS18, RPS19, RPS19BP1, RPS2,RPS20, RPS21, RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS27L, RPS28,RPS29, RPS3, RPS3A, RPS4X, RPS4Y1, RPS4Y2, RPS5, RPS6, RPS6KA1, RPS6KA2,RPS6KA3, RPS6KA4, RPS6KA5, RPS6KA6, RPS6KB1, RPS6KB2, RPS6KC1, RPS6KL1,RPS7, RPS8, RPS9, RPSA, RPTN, RPTOR, RPUSD1, RPUSD2, RPUSD3, RPUSD4,RRAD, RRAGA, RRAGB, RRAGC, RRAGD, RRAS, RRAS2, RRBP1, RREB1, RRH, RRM1,RRM2, RRM2B, RRN3, RRNAD1, RRP1, RRP12, RRP15, RRP1B, RRP36, RRP7A,RRP8, RRP9, RRS1, RS1, RSAD1, RSAD2, RSBN1, RSBN1L, RSC1A1, RSF1, RSG1,RSL1D1, RSL24D1, RSPH1, RSPH10B, RSPH10B2, RSPH14, RSPH3, RSPH4A,RSPH6A, RSPH9, RSPO1, RSPO2, RSPO3, RSPO4, RSPRY1, RSRC1, RSRC2, RSRP1,RSU1, RTBDN, RTCA, RTCB, RTEL1, RTEL1-TNFRSF6B, RTF1, RTFDC1, RTKN,RTKN2, RTL1, RTL10, RTL3, RTL4, RTL5, RTL6, RTL8A, RTL8B, RTL8C, RTL9,RTN1, RTN2, RTN3, RTN4, RTN4IP1, RTN4R, RTN4RL1, RTN4RL2, RTP1, RTP2,RTP3, RTP4, RTP5, RTTN, RUBCN, RUBCNL, RUFY1, RUFY2, RUFY3, RUFY4,RUNDC1, RUNDC3A, RUNDC3B, RUNX1, RUNX1T1, RUNX2, RUNX3, RUSC1, RUSC2,RUVBL1, RUVBL2, RWDD1, RWDD2A, RWDD2B, RWDD3, RWDD4, RXFP1, RXFP2,RXFP3, RXFP4, RXRA, RXRB, RXRG, RYBP, RYK, RYR1, RYR2, RYR3, S100A1,S100A10, S100A11, S100A12, S100A13, S100A14, S100A16, S100A2, S100A3,S100A4, S100A5, S100A6, S100A7, S100A7A, S100A7L2, S100A8, S100A9,S100B, S100G, S100P, S100PBP, S100Z, S1PR1, S1PR2, S1PR3, S1PR4, S1PR5,SAA1, SAA2, SAA2-SAA4, SAA4, SAAL1, SAC3D1, SACM1L, SACS, SAE1, SAFB,SAFB2, SAG, SAGE1, SALL1, SALL2, SALL3, SALL4, SAMD1, SAMD10, SAMD11,SAMD12, SAMD13, SAMD14, SAMD15, SAMD3, SAMD4A, SAMD4B, SAMD5, SAMD7,SAMD8, SAMD9, SAMD9L, SAMHD1, SAMM50, SAMSN1, SAP130, SAP18, SAP25,SAP30, SAP30BP, SAP30L, SAPCD1, SAPCD2, SAR1A, SAR1B, SARAF, SARDH,SARM1, SARNP, SARS, SARS2, SART1, SART3, SASH1, SASH3, SASS6, SAT1,SAT2, SATB1, SATB2, SATL1, SAV1, SAXO1, SAXO2, SAYSD1, SBDS, SBF1, SBF2,SBK1, SBK2, SBK3, SBNO1, SBNO2, SBSN, SBSPON, SC5D, SCAF1, SCAF11,SCAF4, SCAF8, SCAI, SCAMP1, SCAMP2, SCAMP3, SCAMP4, SCAMP5, SCAND1,SCAP, SCAPER, SCARA3, SCARA5, SCARB1, SCARB2, SCARF1, SCARF2, SCART1,SCCPDH, SCD, SCD5, SCEL, SCFD1, SCFD2, SCG2, SCG3, SCG5, SCGB1A1,SCGB1C1, SCGB1C2, SCGB1D1, SCGB1D2, SCGB1D4, SCGB2A1, SCGB2A2, SCGB2B2,SCGB3A1, SCGB3A2, SCGN, SCHIP1, SCIMP, SCIN, SCLT1, SCLY, SCMH1, SCML1,SCML2, SCML4, SCN10A, SCN11A, SCN1A, SCN1B, SCN2A, SCN2B, SCN3A, SCN3B,SCN4A, SCN4B, SCN5A, SCN7A, SCN8A, SCN9A, SCNM1, SCNN1A, SCNN1B, SCNN1D,SCNN1G, SCO1, SC02, SCOC, SCP2, SCP2D1, SCPEP1, SCRG1, SCRIB, SCRN1,SCRN2, SCRN3, SCRT1, SCRT2, SCT, SCTR, SCUBE1, SCUBE2, SCUBE3, SCX,SCYL1, SCYL2, SCYL3, SDAD1, SDC1, SDC2, SDC3, SDC4, SDCBP, SDCBP2,SDCCAG3, SDCCAG8, SDE2, SDF2, SDF2L1, SDF4, SDHA, SDHAF1, SDHAF2,SDHAF3, SDHAF4, SDHB, SDHC, SDHD, SDK1, SDK2, SDR16C5, SDR39U1, SDR42E1,SDR42E2, SDR9C7, SDS, SDSL, SEBOX, SEC11A, SEC11C, SEC13, SEC14L1,SEC14L2, SEC14L3, SEC14L4, SEC14L5, SEC14L6, SEC16A, SEC16B, SEC22A,SEC22B, SEC22C, SEC23A, SEC23B, SEC23IP, SEC24A, SEC24B, SEC24C, SEC24D,SEC31A, SEC31B, SEC61A1, SEC61A2, SEC61B, SEC61G, SEC62, SEC63,SECISBP2, SECISBP2L, SECTM1, SEH1L, SEL1L, SEL1L2, SEL1L3, SELE,SELENBP1, SELENOF, SELENOH, SELENOI, SELENOK, SELENOM, SELENON, SELENOO,SELENOP, SELENOS, SELENOT, SELENOV, SELENOW, SELL, SELP, SELPLG, SEM1,SEMA3A, SEMA3B, SEMA3C, SEMA3D, SEMA3E, SEMA3F, SEMA3G, SEMA4A, SEMA4B,SEMA4C, SEMA4D, SEMA4F, SEMA4G, SEMA5A, SEMA5B, SEMA6A, SEMA6B, SEMA6C,SEMA6D, SEMA7A, SEMG1, SEMG2, SENP1, SENP2, SENP3, SENP3-EIF4A1, SENP5,SENP6, SENP7, SENP8, SEPHS1, SEPHS2, SEPSECS, SEPT1, SEPT10, SEPT11,SEPT12, SEPT14, SEPT2, SEPT3, SEPT4, SEPT5, SEPT6, SEPT7, SEPT8, SEPT9,SERAC1, SERBP1, SERF1A, SERF1B, SERF2, SERGEF, SERHL2, SERINC1, SERINC2,SERINC3, SERINC4, SERINC5, SERP1, SERP2, SERPINA1, SERPINA10, SERPINA11,SERPINA12, SERPINA2, SERPINA3, SERPINA4, SERPINA5, SERPINA6, SERPINA7,SERPINA9, SERPINB1, SERPINB10, SERPINB11, SERPINB12, SERPINB13,SERPINB2, SERPINB3, SERPINB4, SERPINB5, SERPINB6, SERPINB7, SERPINB8,SERPINB9, SERPINC1, SERPIND1, SERPINE1, SERPINE2, SERPINE3, SERPINF1,SERPINF2, SERPING1, SERPINH1, SERPINI1, SERPINI2, SERTAD1, SERTAD2,SERTAD3, SERTAD4, SERTM1, SESN1, SESN2, SESN3, SESTD1, SET, SETBP1,SETD1A, SETD1B, SETD2, SETD3, SETD4, SETD5, SETD6, SETD7, SETD9, SETDB1,SETDB2, SETMAR, SETSIP, SETX, SEZ6, SEZ6L, SEZ6L2, SF1, SF3A1, SF3A2,SF3A3, SF3B1, SF3B2, SF3B3, SF3B4, SF3B5, SF3B6, SFI1, SFMBT1, SFMBT2,SFN, SFPQ, SFR1, SFRP1, SFRP2, SFRP4, SFRP5, SFSWAP, SFT2D1, SFT2D2,SFT2D3, SFTA2, SFTA3, SFTPA1, SFTPA2, SFTPB, SFTPC, SFTPD, SFXN1, SFXN2,SFXN3, SFXN4, SFXN5, SGCA, SGCB, SGCD, SGCE, SGCG, SGCZ, SGF29, SGIP1,SGK1, SGK2, SGK3, SGK494, SGMS1, SGMS2, SGO1, SG02, SGPL1, SGPP1, SGPP2,SGSH, SGSM1, SGSM2, SGSM3, SGTA, SGTB, SH2B1, SH2B2, SH2B3, SH2D1A,SH2D1B, SH2D2A, SH2D3A, SH2D3C, SH2D4A, SH2D4B, SH2D5, SH2D6, SH2D7,SH3BGR, SH3BGRL, SH3BGRL2, SH3BGRL3, SH3BP1, SH3BP2, SH3BP4, SH3BP5,SH3BP5L, SH3D19, SH3D21, SH3GL1, SH3GL2, SH3GL3, SH3GLB1, SH3GLB2,SH3KBP1, SH3PXD2A, SH3PXD2B, SH3RF1, SH3RF2, SH3RF3, SH3TC1, SH3TC2,SH3YL1, SHANK1, SHANK2, SHANK3, SHARPIN, SHB, SHBG, SHC1, SHC2, SHC3,SHC4, SHCBP1, SHCBP1L, SHD, SHE, SHF, SHH, SHISA2, SHISA3, SHISA4,SHISA5, SHISA6, SHISA7, SHISA8, SHISA9, SHKBP1, SHMT1, SHMT2, SHOC2,SHOX, SHOX2, SHPK, SHPRH, SHQ1, SHROOM1, SHROOM2, SHROOM3, SHROOM4,SHTN1, SI, SIAE, SIAH1, SIAH2, SIAH3, SIDT1, SIDT2, SIGIRR, SIGLEC1,SIGLEC10, SIGLEC11, SIGLEC12, SIGLEC14, SIGLEC15, SIGLEC5, SIGLEC6,SIGLEC7, SIGLEC8, SIGLEC9, SIGLECL1, SIGMAR1, SIK1, SIK2, SIK3, SIKE1,SIL1, SIM1, SIM2, SIMC1, SIN3A, SIN3B, SIPA1, SIPA1L1, SIPA1L2, SIPA1L3,SIRPA, SIRPB1, SIRPB2, SIRPD, SIRPG, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5,SIRT6, SIRT7, SIT1, SIVA1, SIX1, SIX2, SIX3, SIX4, SIX5, SIX6, SKA1,SKA2, SKA3, SKAP1, SKAP2, SKI, SKIDA1, SKIL, SKIV2L, SKIV2L2, SKOR1,SKOR2, SKP1, SKP2, SLA, SLA2, SLAIN1, SLAIN2, SLAMF1, SLAMF6, SLAMF7,SLAMF8, SLAMF9, SLBP, SLC10A1, SLC10A2, SLC10A3, SLC10A4, SLC10A5,SLC10A6, SLC10A7, SLC11A1, SLC11A2, SLC12A1, SLC12A2, SLC12A3, SLC12A4,SLC12A5, SLC12A6, SLC12A7, SLC12A8, SLC12A9, SLC13A1, SLC13A2, SLC13A3,SLC13A4, SLC13A5, SLC14A1, SLC14A2, SLC15A1, SLC15A2, SLC15A3, SLC15A4,SLC15A5, SLC16A1, SLC16A10, SLC16A11, SLC16A12, SLC16A13, SLC16A14,SLC16A2, SLC16A3, SLC16A4, SLC16A5, SLC16A6, SLC16A7, SLC16A8, SLC16A9,SLC17A1, SLC17A2, SLC17A3, SLC17A4, SLC17A5, SLC17A6, SLC17A7, SLC17A8,SLC17A9, SLC18A1, SLC18A2, SLC18A3, SLC18B1, SLC19A1, SLC19A2, SLC19A3,SLC1A1, SLC1A2, SLC1A3, SLC1A4, SLC1A5, SLC1A6, SLC1A7, SLC20A1,SLC20A2, SLC22A1, SLC22A10, SLC22A11, SLC22A12, SLC22A13, SLC22A14,SLC22A15, SLC22A16, SLC22A17, SLC22A18, SLC22A18AS, SLC22A2, SLC22A23,SLC22A24, SLC22A25, SLC22A3, SLC22A31, SLC22A4, SLC22A5, SLC22A6,SLC22A7, SLC22A8, SLC22A9, SLC23A1, SLC23A2, SLC23A3, SLC24A1, SLC24A2,SLC24A3, SLC24A4, SLC24A5, SLC25A1, SLC25A10, SLC25A11, SLC25A12,SLC25A13, SLC25A14, SLC25A15, SLC25A16, SLC25A17, SLC25A18, SLC25A19,SLC25A2, SLC25A20, SLC25A21, SLC25A22, SLC25A23, SLC25A24, SLC25A25,SLC25A26, SLC25A27, SLC25A28, SLC25A29, SLC25A3, SLC25A30, SLC25A31,SLC25A32, SLC25A33, SLC25A34, SLC25A35, SLC25A36, SLC25A37, SLC25A38,SLC25A39, SLC25A4, SLC25A40, SLC25A41, SLC25A42, SLC25A43, SLC25A44,SLC25A45, SLC25A46, SLC25A47, SLC25A48, SLC25A5, SLC25A51, SLC25A52,SLC25A53, SLC25A6, SLC26A1, SLC26A10, SLC26A11, SLC26A2, SLC26A3,SLC26A4, SLC26A5, SLC26A6, SLC26A7, SLC26A8, SLC26A9, SLC27A1, SLC27A2,SLC27A3, SLC27A4, SLC27A5, SLC27A6, SLC28A1, SLC28A2, SLC28A3, SLC29A1,SLC29A2, SLC29A3, SLC29A4, SLC2A1, SLC2A10, SLC2A11, SLC2A12, SLC2A13,SLC2A14, SLC2A2, SLC2A3, SLC2A4, SLC2A4RG, SLC2A5, SLC2A6, SLC2A7,SLC2A8, SLC2A9, SLC30A1, SLC30A10, SLC30A2, SLC30A3, SLC30A4, SLC30A5,SLC30A6, SLC30A7, SLC30A8, SLC30A9, SLC31A1, SLC31A2, SLC32A1, SLC33A1,SLC34A1, SLC34A2, SLC34A3, SLC35A1, SLC35A2, SLC35A3, SLC35A4, SLC35A5,SLC35B1, SLC35B2, SLC35B3, SLC35B4, SLC35C1, SLC35C2, SLC35D1, SLC35D2,SLC35D3, SLC35E1, SLC35E2, SLC35E2B, SLC35E3, SLC35E4, SLC35F1, SLC35F2,SLC35F3, SLC35F4, SLC35F5, SLC35F6, SLC35G1, SLC35G2, SLC35G3, SLC35G4,SLC35G5, SLC35G6, SLC36A1, SLC36A2, SLC36A3, SLC36A4, SLC37A1, SLC37A2,SLC37A3, SLC37A4, SLC38A1, SLC38A10, SLC38A11, SLC38A2, SLC38A3,SLC38A4, SLC38A5, SLC38A6, SLC38A7, SLC38A8, SLC38A9, SLC39A1, SLC39A10,SLC39A11, SLC39A12, SLC39A13, SLC39A14, SLC39A2, SLC39A3, SLC39A4,SLC39A5, SLC39A6, SLC39A7, SLC39A8, SLC39A9, SLC3A1, SLC3A2, SLC40A1,SLC41A1, SLC41A2, SLC41A3, SLC43A1, SLC43A2, SLC43A3, SLC44A1, SLC44A2,SLC44A3, SLC44A4, SLC44A5, SLC45A1, SLC45A2, SLC45A3, SLC45A4, SLC46A1,SLC46A2, SLC46A3, SLC47A1, SLC47A2, SLC48A1, SLC4A1, SLC4A10, SLC4A11,SLC4A1AP, SLC4A2, SLC4A3, SLC4A4, SLC4A5, SLC4A7, SLC4A8, SLC4A9,SLC50A1, SLC51A, SLC51B, SLC52A1, SLC52A2, SLC52A3, SLC5A1, SLC5A10,SLC5A11, SLC5A12, SLC5A2, SLC5A3, SLC5A4, SLC5A5, SLC5A6, SLC5A7,SLC5A8, SLC5A9, SLC6A1, SLC6A11, SLC6A12, SLC6A13, SLC6A14, SLC6A15,SLC6A16, SLC6A17, SLC6A18, SLC6A19, SLC6A2, SLC6A20, SLC6A3, SLC6A4,SLC6A5, SLC6A6, SLC6A7, SLC6A8, SLC6A9, SLC7A1, SLC7A10, SLC7A11,SLC7A13, SLC7A14, SLC7A2, SLC7A3, SLC7A4, SLC7A5, SLC7A6, SLC7A6OS,SLC7A7, SLC7A8, SLC7A9, SLC8A1, SLC8A2, SLC8A3, SLC8B1, SLC9A1, SLC9A2,SLC9A3, SLC9A3R1, SLC9A3R2, SLC9A4, SLC9A5, SLC9A6, SLC9A7, SLC9A8,SLC9A9, SLC9B1, SLC9B2, SLC9C1, SLC9C2, SLCO1A2, SLCO1B1, SLCO1B3,SLCO1B7, SLCO1C1, SLCO2A1, SLCO2B1, SLCO3A1, SLCO4A1, SLCO4C1, SLCO5A1,SLCO6A1, SLF1, SLF2, SLFN11, SLFN12, SLFN12L, SLFN13, SLFN14, SLFN5,SLFNL1, SLIRP, SLIT1, SLIT2, SLIT3, SLITRK1, SLITRK2, SLITRK3, SLITRK4,SLITRK5, SLITRK6, SLK, SLMAP, SLN, SLPI, SLTM, SLU7, SLURP1, SLURP2,SLX1A, SLX1B, SLX4, SLX4IP, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6,SMAD7, SMAD9, SMAGP, SMAP1, SMAP2, SMARCA1, SMARCA2, SMARCA4, SMARCA5,SMARCAD1, SMARCAL1, SMARCB1, SMARCC1, SMARCC2, SMARCD1, SMARCD2,SMARCD3, SMARCE1, SMC1A, SMC1B, SMC2, SMC3, SMC4, SMC5, SMC6, SMCHD1,SMCO1, SMCO2, SMCO3, SMCO4, SMCP, SMCR8, SMDT1, SMG1, SMG5, SMG6, SMG7,SMG8, SMG9, SMIM1, SMIM10, SMIM10L1, SMIM10L2A, SMIM10L2B, SMIM11A,SMIM11B, SMIM12, SMIM13, SMIM14, SMIM15, SMIM17, SMIM18, SMIM19, SMIM2,SMIM20, SMIM21, SMIM22, SMIM23, SMIM24, SMIM26, SMIM27, SMIM28, SMIM29,SMIM3, SMIM30, SMIM31, SMIM4, SMIM5, SMIM6, SMIM7, SMIM8, SMIM9, SMKR1,SMLR1, SMN1, SMN2, SMNDC1, SMO, SMOC1, SMOC2, SMOX, SMPD1, SMPD2, SMPD3,SMPD4, SMPDL3A, SMPDL3B, SMPX, SMR3A, SMR3B, SMS, SMTN, SMTNL1, SMTNL2,SMU1, SMUG1, SMURF1, SMURF2, SMYD1, SMYD2, SMYD3, SMYD4, SMYD5, SNAI1,SNAI2, SNAI3, SNAP23, SNAP25, SNAP29, SNAP47, SNAP91, SNAPC1, SNAPC2,SNAPC3, SNAPC4, SNAPC5, SNAPIN, SNCA, SNCAIP, SNCB, SNCG, SND1, SNED1,SNF8, SNHG28, SNIP1, SNN, SNPH, SNRK, SNRNP200, SNRNP25, SNRNP27,SNRNP35, SNRNP40, SNRNP48, SNRNP70, SNRPA, SNRPA1, SNRPB, SNRPB2, SNRPC,SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF, SNRPG, SNRPN, SNTA1, SNTB1, SNTB2,SNTG1, SNTG2, SNTN, SNU13, SNUPN, SNURF, SNW1, SNX1, SNX10, SNX11,SNX12, SNX13, SNX14, SNX15, SNX16, SNX17, SNX18, SNX19, SNX2, SNX20,SNX21, SNX22, SNX24, SNX25, SNX27, SNX29, SNX3, SNX30, SNX31, SNX32,SNX33, SNX4, SNX5, SNX6, SNX7, SNX8, SNX9, SOAT1, SOAT2, SOBP, SOCS1,SOCS2, SOCS3, SOCS4, SOCS5, SOCS6, SOCS7, SOD1, SOD2, SOD3, SOGA1,SOGA3, SOHLH1, SOHLH2, SON, SORBS1, SORBS2, SORBS3, SORCS1, SORCS2,SORCS3, SORD, SORL1, SORT1, SOS1, SOS2, SOST, SOSTDC1, SOWAHA, SOWAHB,SOWAHC, SOWAHD, SOX1, SOX10, SOX11, SOX12, SOX13, SOX14, SOX15, SOX17,SOX18, SOX2, SOX21, SOX3, SOX30, SOX4, SOX5, SOX6, SOX7, SOX8, SOX9,SP1, SP100, SP110, SP140, SP140L, SP2, SP3, SP4, SP5, SP6, SP7, SP8,SP9, SPA17, SPAAR, SPACA1, SPACA3, SPACA4, SPACA5, SPACA5B, SPACA6,SPACA7, SPACA9, SPAG1, SPAG11A, SPAG11B, SPAG16, SPAG17, SPAG4, SPAG5,SPAG6, SPAG7, SPAG8, SPAG9, SPAM1, SPANXA1, SPANXA2, SPANXB1, SPANXC,SPANXD, SPANXN1, SPANXN2, SPANXN3, SPANXN4, SPANXN5, SPARC, SPARCL1,SPART, SPAST, SPATA1, SPATA12, SPATA13, SPATA16, SPATA17, SPATA18,SPATA19, SPATA2, SPATA20, SPATA21, SPATA22, SPATA24, SPATA25, SPATA2L,SPATA3, SPATA31A1, SPATA31A3, SPATA31A5, SPATA31A6, SPATA31A7,SPATA31D1, SPATA31D3, SPATA31D4, SPATA31E1, SPATA32, SPATA33, SPATA4,SPATA45, SPATA46, SPATA5, SPATA5L1, SPATA6, SPATA6L, SPATA7, SPATA8,SPATA9, SPATC1, SPATC1L, SPATS1, SPATS2, SPATS2L, SPC24, SPC25, SPCS1,SPCS2, SPCS3, SPDEF, SPDL1, SPDYA, SPDYC, SPDYE1, SPDYE16, SPDYE2,SPDYE2B, SPDYE3, SPDYE4, SPDYE5, SPDYE6, SPECC1, SPECC1L,SPECC1L-ADORA2A, SPEF1, SPEF2, SPEG, SPEM1, SPEN, SPERT, SPESP1, SPG11,SPG21, SPG7, SPHAR, SPHK1, SPHK2, SPHKAP, SPI1, SPIB, SPIC, SPICE1,SPIDR, SPIN1, SPIN2A, SPIN2B, SPIN3, SPIN4, SPINK1, SPINK13, SPINK14,SPINK2, SPINK4, SPINK5, SPINK6, SPINK7, SPINK8, SPINK9, SPINT1, SPINT2,SPINT3, SPINT4, SPIRE1, SPIRE2, SPN, SPNS1, SPNS2, SPNS3, SPO11, SPOCD1,SPOCK1, SPOCK2, SPOCK3, SPON1, SPON2, SPOP, SPOPL, SPOUT1, SPP1, SPP2,SPPL2A, SPPL2B, SPPL2C, SPPL3, SPR, SPRED1, SPRED2, SPRED3, SPRN,SPRR1A, SPRR1B, SPRR2A, SPRR2B, SPRR2D, SPRR2E, SPRR2F, SPRR2G, SPRR3,SPRR4, SPRR5, SPRTN, SPRY1, SPRY2, SPRY3, SPRY4, SPRYD3, SPRYD4, SPRYD7,SPSB1, SPSB2, SPSB3, SPSB4, SPTA1, SPTAN1, SPTB, SPTBN1, SPTBN2, SPTBN4,SPTBN5, SPTLC1, SPTLC2, SPTLC3, SPTSSA, SPTSSB, SPTY2D1, SPTY2D1-AS1,SPX, SPZ1, SQLE, SQOR, SQSTM1, SRA1, SRBD1, SRC, SRCAP, SRCIN1, SRD5A1,SRD5A2, SRD5A3, SREBF1, SREBF2, SREK1, SREK1IP1, SRF, SRFBP1, SRGAP1,SRGAP2, SRGAP2B, SRGAP2C, SRGAP3, SRGN, SRI, SRL, SRM, SRMS, SRP14,SRP19, SRP54, SRP68, SRP72, SRP9, SRPK1, SRPK2, SRPK3, SRPRA, SRPRB,SRPX, SRPX2, SRR, SRRD, SRRM1, SRRM2, SRRM3, SRRM4, SRRM5, SRRT, SRSF1,SRSF10, SRSF11, SRSF12, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7, SRSF8,SRSF9, SRXN1, SRY, SS18, SS18L1, SS18L2, SSB, SSBP1, SSBP2, SSBP3,SSBP4, SSC4D, SSC5D, SSFA2, SSH1, SSH2, SSH3, SSMEM1, SSNA1, SSPN, SSPO,SSR1, SSR2, SSR3, SSR4, SSRP1, SSSCA1, SST, SSTR1, SSTR2, SSTR3, SSTR4,SSTR5, SSU72, SSU72P8, SSUH2, SSX1, SSX2, SSX2B, SSX2IP, SSX3, SSX4,SSX4B, SSX5, SSX7, ST13, ST14, ST18, ST20, ST20-MTHFS, ST3GAL1, ST3GAL2,ST3GAL3, ST3GAL4, ST3GAL5, ST3GAL6, ST5, ST6GAL1, ST6GAL2, ST6GALNAC1,ST6GALNAC2, ST6GALNAC3, ST6GALNAC4, ST6GALNAC5, ST6GALNAC6, ST7, ST7L,ST8SIA1, ST8SIA2, ST8SIA3, ST8SIA4, ST8SIA5, ST8SIA6, STAB1, STAB2,STAC, STAC2, STAC3, STAG1, STAG2, STAG3, STAM, STAM2, STAMBP, STAMBPL1,STAP1, STAP2, STAR, STARD10, STARD13, STARD3, STARD3NL, STARD4, STARD5,STARD6, STARD7, STARD8, STARD9, STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, STAT6, STATH, STAU1, STAU2, STBD1, STC1, STC2, STEAP1, STEAP1B,STEAP2, STEAP3, STEAP4, STH, STIL, STIM1, STIM2, STIP1, STK10, STK11,STK11IP, STK16, STK17A, STK17B, STK19, STK24, STK25, STK26, STK3, STK31,STK32A, STK32B, STK32C, STK33, STK35, STK36, STK38, STK38L, STK39, STK4,STK40, STKLD1, STMN1, STMN2, STMN3, STMN4, STMND1, STN1, STOM, STOML1,STOML2, STOML3, STON1, STON1-GTF2A1L, STON2, STOX1, STOX2, STPG1, STPG2,STPG3, STPG4, STRA6, STRA8, STRADA, STRADB, STRAP, STRBP, STRC, STRIP1,STRIP2, STRN, STRN3, STRN4, STS, STT3A, STT3B, STUB1, STUM, STX10,STX11, STX12, STX16, STX16-NPEPL1, STX17, STX18, STX19, STX1A, STX1B,STX2, STX3, STX4, STX5, STX6, STX7, STX8, STXBP1, STXBP2, STXBP3,STXBP4, STXBP5, STXBP5L, STXBP6, STYK1, STYX, STYXL1, SUB1, SUCLA2,SUCLG1, SUCLG2, SUCNR1, SUCO, SUDS3, SUFU, SUGCT, SUGP1, SUGP2, SUGT1,SULF1, SULF2, SULT1A1, SULT1A2, SULT1A3, SULT1A4, SULT1B1, SULT1C2,SULT1C3, SULT1C4, SULT1E1, SULT2A1, SULT2B1, SULT4A1, SULT6B1, SUMF1,SUMF2, SUMO1, SUMO2, SUMO3, SUMO4, SUN1, SUN2, SUN3, SUN5, SUOX,SUPT16H, SUPT20H, SUPT3H, SUPT4H1, SUPT5H, SUPT6H, SUPT7L, SUPV3L1,SURF1, SURF2, SURF4, SURF6, SUSD1, SUSD2, SUSD3, SUSD4, SUSD5, SUSD6,SUV39H1, SUV39H2, SUZ12, SV2A, SV2B, SV2C, SVBP, SVEP1, SVIL, SVIP,SVOP, SVOPL, SWAP70, SWI5, SWSAP1, SWT1, SYAP1, SYBU, SYCE1, SYCE1L,SYCE2, SYCE3, SYCN, SYCP1, SYCP2, SYCP2L, SYCP3, SYDE1, SYDE2, SYF2,SYK, SYMPK, SYN1, SYN2, SYN3, SYNC, SYNCRIP, SYNDIG1, SYNDIG1L, SYNE1,SYNE2, SYNE3, SYNE4, SYNGAP1, SYNGR1, SYNGR2, SYNGR3, SYNGR4, SYNJ1,SYNJ2, SYNJ2BP, SYNJ2BP-COX16, SYNM, SYNPO, SYNPO2, SYNPO2L, SYNPR,SYNRG, SYP, SYPL1, SYPL2, SYS1, SYS1-DBNDD2, SYT1, SYT10, SYT11, SYT12,SYT13, SYT14, SYT15, SYT16, SYT17, SYT2, SYT3, SYT4, SYT5, SYT6, SYT7,SYT8, SYT9, SYTL1, SYTL2, SYTL3, SYTL4, SYTL5, SYVN1, SZRD1, SZT2, T,TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9, TAB1, TAB2, TAB3, TAC1, TAC3,TAC4, TACC1, TACC2, TACC3, TACO1, TACR1, TACR2, TACR3, TACSTD2, TADA1,TADA2A, TADA2B, TADA3, TAF1, TAF10, TAF11, TAF12, TAF13, TAF15, TAF1A,TAF1B, TAF1C, TAF1D, TAF1L, TAF2, TAF3, TAF4, TAF4B, TAF5, TAF5L, TAF6,TAF6L, TAF7, TAF7L, TAF8, TAF9, TAF9B, TAGAP, TAGLN, TAGLN2, TAGLN3,TAL1, TAL2, TALDO1, TAMM41, TANC1, TANC2, TANGO2, TANGO6, TANK, TAOK1,TAOK2, TAOK3, TAP1, TAP2, TAPBP, TAPBPL, TAPT1, TARBP1, TARBP2, TARDBP,TARM1, TARS, TARS2, TARSL2, TAS1R1, TAS1R2, TAS1R3, TAS2R1, TAS2R10,TAS2R13, TAS2R14, TAS2R16, TAS2R19, TAS2R20, TAS2R3, TAS2R30, TAS2R31,TAS2R38, TAS2R39, TAS2R4, TAS2R40, TAS2R41, TAS2R42, TAS2R43, TAS2R46,TAS2R5, TAS2R50, TAS2R60, TAS2R7, TAS2R8, TAS2R9, TASP1, TAT, TATDN1,TATDN2, TATDN3, TAX1BP1, TAX1BP3, TAZ, TBATA, TBC1D1, TBC1D10A,TBC1D10B, TBC1D10C, TBC1D12, TBC1D13, TBC1D14, TBC1D15, TBC1D16,TBC1D17, TBC1D19, TBC1D2, TBC1D20, TBC1D21, TBC1D22A, TBC1D22B, TBC1D23,TBC1D24, TBC1D25, TBC1D26, TBC1D28, TBC1D29, TBC1D2B, TBC1D3, TBC1D30,TBC1D31, TBC1D32, TBC1D3B, TBC1D3C, TBC1D3D, TBC1D3E, TBC1D3F, TBC1D3G,TBC1D3H, TBC1D3I, TBC1D3K, TBC1D3L, TBC1D4, TBC1D5, TBC1D7, TBC1D8,TBC1D8B, TBC1D9, TBC1D9B, TBCA, TBCB, TBCC, TBCCD1, TBCD, TBCE, TBCEL,TBCK, TBK1, TBKBP1, TBL1X, TBL1XR1, TBL1Y, TBL2, TBL3, TBP, TBPL1,TBPL2, TBR1, TBRG1, TBRG4, TBX1, TBX10, TBX15, TBX18, TBX19, TBX2,TBX20, TBX21, TBX22, TBX3, TBX4, TBX5, TBX6, TBXA2R, TBXAS1, TC2N,TCAF1, TCAF2, TCAIM, TCAP, TCEA1, TCEA2, TCEA3, TCEAL1, TCEAL2, TCEAL3,TCEAL4, TCEAL5, TCEAL6, TCEAL7, TCEAL8, TCEAL9, TCEANC, TCEANC2, TCERG1,TCERG1L, TCF12, TCF15, TCF19, TCF20, TCF21, TCF23, TCF24, TCF25, TCF3,TCF4, TCF7, TCF7L1, TCF7L2, TCFL5, TCHH, TCHHL1, TCHP, TCIRG1, TCL1A,TCL1B, TCN1, TCN2, TCOF1, TCP1, TCP10, TCP10L, TCP10L2, TCP11, TCP11L1,TCP11L2, TCP11X2, TCTA, TCTE1, TCTE3, TCTEX1D1, TCTEX1D2, TCTEX1D4,TCTN1, TCTN2, TCTN3, TDG, TDGF1, TDO2, TDP1, TDP2, TDRD1, TDRD10,TDRD12, TDRD15, TDRD3, TDRD5, TDRD6, TDRD7, TDRD9, TDRKH, TDRP, TEAD1,TEAD2, TEAD3, TEAD4, TEC, TECPR1, TECPR2, TECR, TECRL, TECTA, TECTB,TEDDM1, TEF, TEFM, TEK, TEKT1, TEKT2, TEKT3, TEKT4, TEKT5, TELO2, TEN1,TEN1-CDK3, TENM1, TENM2, TENM3, TENM4, TEP1, TEPP, TEPSIN, TERB1, TERB2,TERF1, TERF2, TERF2IP, TERT, TES, TESC, TESK1, TESK2, TESMIN, TESPA1,TET1, TET2, TET3, TEX10, TEX101, TEX11, TEX12, TEX13A, TEX13B, TEX13C,TEX13D, TEX14, TEX15, TEX19, TEX2, TEX22, TEX26, TEX261, TEX264, TEX28,TEX29, TEX30, TEX33, TEX35, TEX36, TEX37, TEX38, TEX43, TEX44, TEX45,TEX46, TEX47, TEX48, TEX49, TEX50, TEX51, TEX9, TF, TFAM, TFAP2A,TFAP2B, TFAP2C, TFAP2D, TFAP2E, TFAP4, TFB1M, TFB2M, TFCP2, TFCP2L1,TFDP1, TFDP2, TFDP3, TFE3, TFEB, TFEC, TFF1, TFF2, TFF3, TFG, TFIP11,TFPI, TFPI2, TFPT, TFR2, TFRC, TG, TGDS, TGFA, TGFB1, TGFB1I1, TGFB2,TGFB3, TGFBI, TGFBR1, TGFBR2, TGFBR3, TGFBR3L, TGFBRAP1, TGIF1, TGIF2,TGIF2-C20orf24, TGIF2LX, TGIF2LY, TGM1, TGM2, TGM3, TGM4, TGM5, TGM6,TGM7, TGOLN2, TGS1, TH, THADA, THAP1, THAP10, THAP11, THAP12, THAP2,THAP3, THAP4, THAP5, THAP6, THAP7, THAP8, THAP9, THBD, THBS1, THBS2,THBS3, THBS4, THEG, THEGL, THEM4, THEM5, THEM6, THEMIS, THEMIS2, THG1L,THNSL1, THNSL2, THOC1, THOC2, THOC3, THOC5, THOC6, THOC7, THOP1, THPO,THRA, THRAP3, THRB, THRSP, THSD1, THSD4, THSD7A, THSD7B, THTPA, THUMPD1,THUMPD2, THUMPD3, THY1, THYN1, TIA1, TIAF1, TIAL1, TIAM1, TIAM2, TICAM1,TICAM2, TICRR, TIE1, TIFA, TIFAB, TIGAR, TIGD1, TIGD2, TIGD3, TIGD4,TIGD5, TIGD6, TIGD7, TIGIT, TIMD4, TIMELESS, TIMM10, TIMM10B, TIMM13,TIMM17A, TIMM17B, TIMM21, TIMM22, TIMM23, TIMM23B, TIMM29, TIMM44,TIMM50, TIMM8A, TIMM8B, TIMM9, TIMMDC1, TIMP1, TIMP2, TIMP3, TIMP4,TINAG, TINAGL1, TINCR, TINF2, TIPARP, TIPIN, TIPRL, TIRAP, TISP43,TJAP1, TJP1, TJP2, TJP3, TK1, TK2, TKFC, TKT, TKTL1, TKTL2, TLCD1,TLCD2, TLDC1, TLDC2, TLE1, TLE2, TLE3, TLE4, TLE6, TLK1, TLK2, TLL1,TLL2, TLN1, TLN2, TLNRD1, TLR1, TLR10, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLX1, TLX2, TLX3, TM2D1, TM2D2, TM2D3, TM4SF1,TM4SF18, TM4SF19, TM4SF19-TCTEX1D2, TM4SF20, TM4SF4, TM4SF5, TM6SF1,TM6SF2, TM7SF2, TM7SF3, TM9SF1, TM9SF2, TM9SF3, TM9SF4, TMA16, TMA7,TMBIM1, TMBIM4, TMBIM6, TMC1, TMC2, TMC3, TMC4, TMC5, TMC6, TMC7, TMC8,TMCC1, TMCC2, TMCC3, TMCO1, TMCO2, TMCO3, TMCO4, TMCO5A, TMCO6, TMED1,TMED10, TMED2, TMED3, TMED4, TMED5, TMED6, TMED7, TMED7-TICAM2, TMED8,TMED9, TMEFF1, TMEFF2, TMEM100, TMEM101, TMEM102, TMEM104, TMEM105,TMEM106A, TMEM106B, TMEM106C, TMEM107, TMEM108, TMEM109, TMEM11,TMEM110, TMEM110-MUSTN1, TMEM114, TMEM115, TMEM116, TMEM117, TMEM119,TMEM120A, TMEM120B, TMEM121, TMEM121B, TMEM123, TMEM125, TMEM126A,TMEM126B, TMEM127, TMEM128, TMEM129, TMEM130, TMEM131, TMEM131L,TMEM132A, TMEM132B, TMEM132C, TMEM132D, TMEM132E, TMEM133, TMEM134,TMEM135, TMEM136, TMEM138, TMEM139, TMEM140, TMEM141, TMEM143, TMEM144,TMEM145, TMEM147, TMEM14A, TMEM14B, TMEM14C, TMEM150A, TMEM150B,TMEM150C, TMEM151A, TMEM151B, TMEM154, TMEM155, TMEM156, TMEM158,TMEM159, TMEM160, TMEM161A, TMEM161B, TMEM163, TMEM164, TMEM165,TMEM167A, TMEM167B, TMEM168, TMEM169, TMEM17, TMEM170A, TMEM170B,TMEM171, TMEM173, TMEM174, TMEM175, TMEM176A, TMEM176B, TMEM177,TMEM178A, TMEM178B, TMEM179, TMEM179B, TMEM18, TMEM181, TMEM182,TMEM183A, TMEM184A, TMEM184B, TMEM184C, TMEM185A, TMEM185B, TMEM186,TMEM187, TMEM189, TMEM189-UBE2V1, TMEM19, TMEM190, TMEM191B, TMEM191C,TMEM192, TMEM196, TMEM198, TMEM199, TMEM2, TMEM200A, TMEM200B, TMEM200C,TMEM201, TMEM202, TMEM203, TMEM204, TMEM205, TMEM206, TMEM207, TMEM208,TMEM209, TMEM210, TMEM211, TMEM212, TMEM213, TMEM214, TMEM215, TMEM216,TMEM217, TMEM218, TMEM219, TMEM220, TMEM221, TMEM222, TMEM223, TMEM225,TMEM225B, TMEM229A, TMEM229B, TMEM230, TMEM231, TMEM232, TMEM233,TMEM234, TMEM235, TMEM236, TMEM237, TMEM238, TMEM239, TMEM240, TMEM241,TMEM242, TMEM243, TMEM244, TMEM245, TMEM246, TMEM247, TMEM248, TMEM249,TMEM25, TMEM250, TMEM251, TMEM252, TMEM253, TMEM254, TMEM255A, TMEM255B,TMEM256, TMEM256-PLSCR3, TMEM257, TMEM258, TMEM259, TMEM26, TMEM260,TMEM262, TMEM263, TMEM265, TMEM266, TMEM267, TMEM268, TMEM269, TMEM27,TMEM270, TMEM30A, TMEM30B, TMEM31, TMEM33, TMEM35A, TMEM35B, TMEM37,TMEM38A, TMEM38B, TMEM39A, TMEM39B, TMEM40, TMEM41A, TMEM41B, TMEM42,TMEM43, TMEM44, TMEM45A, TMEM45B, TMEM47, TMEM5, TMEM50A, TMEM50B,TMEM51, TMEM52, TMEM52B, TMEM53, TMEM54, TMEM55A, TMEM55B, TMEM56,TMEM56-RWDD3, TMEM57, TMEM59, TMEM59L, TMEM60, TMEM61, TMEM62, TMEM63A,TMEM63B, TMEM63C, TMEM64, TMEM65, TMEM67, TMEM68, TMEM69, TMEM70,TMEM71, TMEM72, TMEM74, TMEM74B, TMEM78, TMEM79, TMEM80, TMEM81, TMEM82,TMEM86A, TMEM86B, TMEM87A, TMEM87B, TMEM88, TMEM88B, TMEM89, TMEM8A,TMEM8B, TMEM9, TMEM91, TMEM92, TMEM94, TMEM95, TMEM97, TMEM98, TMEM99,TMEM9B, TMF1, TMIE, TMIGD1, TMIGD2, TMIGD3, TMLHE, TMOD1, TMOD2, TMOD3,TMOD4, TMPO, TMPPE, TMPRSS11A, TMPRSS11B, TMPRSS11D, TMPRSS11E,TMPRSS11F, TMPRSS12, TMPRSS13, TMPRSS15, TMPRSS2, TMPRSS3, TMPRSS4,TMPRSS4-AS1, TMPRSS5, TMPRSS6, TMPRSS7, TMPRSS9, TMSB10, TMSB15A,TMSB15B, TMSB4X, TMSB4Y, TMTC1, TMTC2, TMTC3, TMTC4, TMUB1, TMUB2, TMX1,TMX2, TMX2-CTNND1, TMX3, TMX4, TNC, TNF, TNFAIP1, TNFAIP2, TNFAIP3,TNFAIP6, TNFAIP8, TNFAIP8L1, TNFAIP8L2, TNFAIP8L3, TNFRSF10A, TNFRSF10B,TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B, TNFRSF12A, TNFRSF13B,TNFRSF13C, TNFRSF14, TNFRSF17, TNFRSF18, TNFRSF19, TNFRSF1A, TNFRSF1B,TNFRSF21, TNFRSF25, TNFRSF4, TNFRSF6B, TNFRSF8, TNFRSF9, TNFSF10,TNFSF11, TNFSF12, TNFSF12-TNFSF13, TNFSF13, TNFSF13B, TNFSF14, TNFSF15,TNFSF18, TNFSF4, TNFSF8, TNFSF9, TNIK, TNIP1, TNIP2, TNIP3, TNK1, TNK2,TNKS, TNKS1BP1, TNKS2, TNMD, TNN, TNNC1, TNNC2, TNNI1, TNNI2, TNNI3,TNNI3K, TNNT1, TNNT2, TNNT3, TNP1, TNP2, TNPO1, TNPO2, TNPO3, TNR,TNRC18, TNRC6A, TNRC6B, TNRC6C, TNS1, TNS2, TNS3, TNS4, TNXB, TOB1,TOB2, TOE1, TOGARAM1, TOGARAM2, TOLLIP, TOM1, TOM1L1, TOM1L2, TOMM20,TOMM20L, TOMM22, TOMM34, TOMM40, TOMM40L, TOMM5, TOMM6, TOMM7, TOMM70,TONSL, TOP1, TOP1MT, TOP2A, TOP2B, TOP3A, TOP3B, TOPAZ1, TOPBP1, TOPORS,TOR1A, TOR1AIP1, TOR1AIP2, TOR1B, TOR2A, TOR3A, TOR4A, TOX, TOX2, TOX3,TOX4, TP53, TP53AIP1, TP53BP1, TP53BP2, TP53I11, TP53I13, TP53I3,TP53INP1, TP53INP2, TP53RK, TP53TG3, TP53TG3B, TP53TG3C, TP53TG3D,TP53TG3E, TP53TG3F, TP53TG5, TP63, TP73, TPBG, TPBGL, TPCN1, TPCN2,TPD52, TPD52L1, TPD52L2, TPD52L3, TPGS1, TPGS2, TPH1, TPH2, TPI1, TPK1,TPM1, TPM2, TPM3, TPM4, TPMT, TPO, TPP1, TPP2, TPPP, TPPP2, TPPP3, TPR,TPRA1, TPRG1, TPRG1L, TPRKB, TPRN, TPRX1, TPSAB1, TPSB2, TPSD1, TPSG1,TPST1, TPST2, TPT1, TPTE, TPTE2, TPX2, TRA2A, TRA2B, TRABD, TRABD2A,TRABD2B, TRAC, TRADD, TRAF1, TRAF2, TRAF3, TRAF3IP1, TRAF3IP2, TRAF3IP3,TRAF4, TRAF5, TRAF6, TRAF7, TRAFD1, TRAIP, TRAJ1, TRAJ10, TRAJ11,TRAJ12, TRAJ13, TRAJ14, TRAJ16, TRAJ17, TRAJ18, TRAJ19, TRAJ2, TRAJ20,TRAJ21, TRAJ22, TRAJ23, TRAJ24, TRAJ25, TRAJ26, TRAJ27, TRAJ28, TRAJ29,TRAJ3, TRAJ30, TRAJ31, TRAJ32, TRAJ33, TRAJ34, TRAJ35, TRAJ36, TRAJ37,TRAJ38, TRAJ39, TRAJ4, TRAJ40, TRAJ41, TRAJ42, TRAJ43, TRAJ44, TRAJ45,TRAJ46, TRAJ47, TRAJ48, TRAJ49, TRAJ5, TRAJ50, TRAJ52, TRAJ53, TRAJ54,TRAJ56, TRAJ57, TRAJ58, TRAJ59, TRAJ6, TRAJ61, TRAJ7, TRAJ9, TRAK1,TRAK2, TRAM1, TRAM1L1, TRAM2, TRANK1, TRAP1, TRAPPC1, TRAPPC10,TRAPPC11, TRAPPC12, TRAPPC13, TRAPPC2, TRAPPC2L, TRAPPC3, TRAPPC3L,TRAPPC4, TRAPPC5, TRAPPC6A, TRAPPC6B, TRAPPC8, TRAPPC9, TRAT1, TRAV10,TRAV1-1, TRAV1-2, TRAV12-1, TRAV12-2, TRAV12-3, TRAV13-1, TRAV13-2,TRAV14DV4, TRAV16, TRAV17, TRAV18, TRAV19, TRAV2, TRAV20, TRAV21,TRAV22, TRAV23DV6, TRAV24, TRAV25, TRAV26-1, TRAV26-2, TRAV27,TRAV29DV5, TRAV3, TRAV30, TRAV34, TRAV36DV7, TRAV38-1, TRAV38-2DV8,TRAV39, TRAV4, TRAV40, TRAV41, TRAV5, TRAV6, TRAV7, TRAV8-1, TRAV8-2,TRAV8-3, TRAV8-4, TRAV8-6, TRAV8-7, TRAV9-1, TRAV9-2, TRBC2, TRBJ2-1,TRBJ2-2, TRBJ2-2P, TRBJ2-3, TRBJ2-4, TRBJ2-5, TRBJ2-6, TRBJ2-7,TRBV10-1, TRBV10-2, TRBV10-3, TRBV11-1, TRBV19, TRBV2, TRBV20-1,TRBV200R9-2, TRBV21OR9-2, TRBV23-1, TRBV230R9-2, TRBV24-1, TRBV25-1,TRBV27, TRBV28, TRBV29-1, TRBV30, TRBV3-1, TRBV4-1, TRBV4-2, TRBV5-1,TRBV5-3, TRBV5-4, TRBV5-5, TRBV5-6, TRBV5-7, TRBV6-1, TRBV6-4, TRBV6-5,TRBV6-6, TRBV6-7, TRBV6-8, TRBV7-1, TRBV7-3, TRBV7-4, TRBV7-6, TRBV7-7,TRBV7-9, TRBV9, TRDC, TRDD1, TRDD2, TRDD3, TRDJ1, TRDJ2, TRDJ3, TRDJ4,TRDMT1, TRDN, TRDV1, TRDV2, TRDV3, TREH, TREM1, TREM2, TREML1, TREML2,TREML4, TRERF1, TREX1, TREX2, TRGC1, TRGC2, TRGJ1, TRGJ2, TRGJP, TRGJP1,TRGJP2, TRGV1, TRGV10, TRGV11, TRGV2, TRGV3, TRGV4, TRGV5, TRGV8, TRGV9,TRH, TRHDE, TRHR, TRIAP1, TRIB1, TRIB2, TRIB3, TRIL, TRIM10, TRIM11,TRIM13, TRIM14, TRIM15, TRIM16, TRIM16L, TRIM17, TRIM2, TRIM21, TRIM22,TRIM23, TRIM24, TRIM25, TRIM26, TRIM27, TRIM28, TRIM29, TRIM3, TRIM31,TRIM32, TRIM33, TRIM34, TRIM35, TRIM36, TRIM37, TRIM38, TRIM39,TRIM39-RPP21, TRIM4, TRIM40, TRIM41, TRIM42, TRIM43, TRIM43B, TRIM44,TRIM45, TRIM46, TRIM47, TRIM48, TRIM49, TRIM49B, TRIM49C, TRIM49D1,TRIM49D2, TRIM5, TRIM50, TRIM51, TRIM52, TRIM54, TRIM55, TRIM56, TRIM58,TRIM59, TRIM6, TRIM60, TRIM61, TRIM62, TRIM63, TRIM64, TRIM64B, TRIM64C,TRIM65, TRIM66, TRIM67, TRIM68, TRIM69, TRIM6-TRIM34, TRIM7, TRIM71,TRIM72, TRIM73, TRIM74, TRIM75P, TRIM77, TRIM8, TRIM9, TRIML1, TRIML2,TRIO, TRIOBP, TRIP10, TRIP11, TRIP12, TRIP13, TRIP4, TRIP6, TRIQK, TRIR,TRIT1, TRMO, TRMT1, TRMT10A, TRMT10B, TRMT10C, TRMT11, TRMT112, TRMT12,TRMT13, TRMT1L, TRMT2A, TRMT2B, TRMT44, TRMT5, TRMT6, TRMT61A, TRMT61B,TRMU, TRNAU1AP, TRNP1, TRNT1, TRO, TROAP, TROVE2, TRPA1, TRPC1, TRPC3,TRPC4, TRPC4AP, TRPC5, TRPC5OS, TRPC6, TRPC7, TRPM1, TRPM2, TRPM3,TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPS1, TRPT1, TRPV1, TRPV2, TRPV3,TRPV4, TRPV5, TRPV6, TRRAP, TRUB1, TRUB2, TSACC, TSC1, TSC2, TSC22D1,TSC22D2, TSC22D3, TSC22D4, TSEN15, TSEN2, TSEN34, TSEN54, TSFM, TSG101,TSGA10, TSGA10IP, TSGA13, TSHB, TSHR, TSHZ1, TSHZ2, TSHZ3, TSKS, TSKU,TSLP, TSN, TSNARE1, TSNAX, TSNAX-DISC1, TSNAXIP1, TSPAN1, TSPAN10,TSPAN11, TSPAN12, TSPAN13, TSPAN14, TSPAN15, TSPAN16, TSPAN17, TSPAN18,TSPAN19, TSPAN2, TSPAN3, TSPAN31, TSPAN32, TSPAN33, TSPAN4, TSPAN5,TSPAN6, TSPAN7, TSPAN8, TSPAN9, TSPEAR, TSPO, TSPO2, TSPOAP1, TSPY1,TSPY10, TSPY2, TSPY3, TSPY4, TSPY8, TSPYL1, TSPYL2, TSPYL4, TSPYL5,TSPYL6, TSR1, TSR2, TSR3, TSSC4, TSSK1B, TSSK2, TSSK3, TSSK4, TSSK6,TST, TSTA3, TSTD1, TSTD2, TSTD3, TTBK1, TTBK2, TTC1, TTC12, TTC13,TTC14, TTC16, TTC17, TTC19, TTC21A, TTC21B, TTC22, TTC23, TTC23L, TTC24,TTC25, TTC26, TTC27, TTC28, TTC29, TTC3, TTC30A, TTC30B, TTC31, TTC32,TTC33, TTC34, TTC36, TTC37, TTC38, TTC39A, TTC39B, TTC39C, TTC4, TTC5,TTC6, TTC7A, TTC7B, TTC8, TTC9, TTC9B, TTC9C, TTF1, TTF2, TTI1, TTI2,TTK, TTL, TTLL1, TTLL10, TTLL11, TTLL12, TTLL13P, TTLL2, TTLL3, TTLL4,TTLL5, TTLL6, TTLL7, TTLL8, TTLL9, TTN, TTPA, TTPAL, TTR, TTYH1, TTYH2,TTYH3, TUB, TUBA1A, TUBA1B, TUBA1C, TUBA3C, TUBA3D, TUBA3E, TUBA4A,TUBA4B, TUBA8, TUBAL3, TUBB, TUBB1, TUBB2A, TUBB2B, TUBB3, TUBB4A,TUBB4B, TUBB6, TUBB8, TUBD1, TUBE1, TUBG1, TUBG2, TUBGCP2, TUBGCP3,TUBGCP4, TUBGCP5, TUBGCP6, TUFM, TUFT1, TULP1, TULP2, TULP3, TULP4,TUNAR, TUSC1, TUSC2, TUSC3, TUSC5, TUT1, TVP23A, TVP23B, TVP23C,TVP23C-CDRT4, TWF1, TWF2, TWIST1, TWIST2, TWISTNB, TWNK, TWSG1, TXK,TXLNA, TXLNB, TXLNG, TXN, TXN2, TXNDC11, TXNDC12, TXNDC15, TXNDC16,TXNDC17, TXNDC2, TXNDC5, TXNDC8, TXNDC9, TXNIP, TXNL1, TXNL4A, TXNL4B,TXNRD1, TXNRD2, TXNRD3, TXNRD3NB, TYK2, TYMP, TYMS, TYR, TYRO3, TYROBP,TYRP1, TYSND1, TYW1, TYW1B, TYW3, TYW5, U2AF1, U2AF1L4, U2AF1L5, U2AF2,U2SURP, UACA, UAP1, UAP1L1, UBA1, UBA2, UBA3, UBA5, UBA52, UBA6, UBA7,UBAC1, UBAC2, UBALD1, UBALD2, UBAP1, UBAP1L, UBAP2, UBAP2L, UBASH3A,UBASH3B, UBB, UBC, UBD, UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3,UBE2D4, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2F-SCLY, UBE2G1, UBE2G2,UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L5P, UBE2L6, UBE2M,UBE2N, UBE2NL, UBE20, UBE2Q1, UBE2Q2, UBE2Q2L, UBE2QL1, UBE2R2, UBE2S,UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, UBE3A, UBE3B, UBE3C, UBE3D,UBE4A, UBE4B, UBFD1, UBIAD1, UBL3, UBL4A, UBL4B, UBL5, UBL7, UBLCP1,UBN1, UBN2, UBOX5, UBP1, UBQLN1, UBQLN2, UBQLN3, UBQLN4, UBQLNL, UBR1,UBR2, UBR3, UBR4, UBR5, UBR7, UBTD1, UBTD2, UBTF, UBTFL1, UBXN1, UBXN10,UBXN11, UBXN2A, UBXN2B, UBXN4, UBXN6, UBXN7, UBXN8, UCHL1, UCHL3, UCHL5,UCK1, UCK2, UCKL1, UCMA, UCN, UCN2, UCN3, UCP1, UCP2, UCP3, UEVLD, UFC1,UFD1, UFL1, UFM1, UFSP1, UFSP2, UGCG, UGDH, UGGT1, UGGT2, UGP2, UGT1A1,UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT2A1,UGT2A2, UGT2A3, UGT2B10, UGT2B11, UGT2B15, UGT2B17, UGT2B28, UGT2B4,UGT2B7, UGT3A1, UGT3A2, UGT8, UHMK1, UHRF1, UHRF1BP1, UHRF1BP1L, UHRF2,UIMC1, ULBP1, ULBP2, ULBP3, ULK1, ULK2, ULK3, ULK4, UMAD1, UMOD, UMODL1,UMPS, UNC119, UNC119B, UNC13A, UNC13B, UNC13C, UNC13D, UNC45A, UNC45B,UNC50, UNC5A, UNC5B, UNC5C, UNC5CL, UNC5D, UNC79, UNC80, UNC93A,UNC93B1, UNCX, UNG, UNK, UNKL, UPB1, UPF1, UPF2, UPF3A, UPF3B, UPK1A,UPK1B, UPK2, UPK3A, UPK3B, UPK3BL1, UPP1, UPP2, UPRT, UQCC1, UQCC2,UQCC3, UQCR10, UQCR11, UQCRB, UQCRC1, UQCRC2, UQCRF S1, UQCRH, UQCRHL,UQCRQ, URAD, URB1, URB2, URGCP, URGCP-MRPS24, URI1, URM1, UROC1, UROD,UROS, USB1, USE1, USF1, USF2, USF3, USH1C, USH1G, USH2A, USHBP1, USMG5,USO1, USP1, USP10, USP11, USP12, USP13, USP14, USP15, USP16, USP17L1,USP17L10, USP17L11, USP17L12, USP17L13, USP17L15, USP17L17, USP17L18,USP17L19, USP17L2, USP17L20, USP17L21, USP17L22, USP17L23, USP17L24,USP17L25, USP17L26, USP17L27, USP17L28, USP17L29, USP17L3, USP17L30,USP17L4, USP17L5, USP17L7, USP17L8, USP18, USP19, USP2, USP20, USP21,USP22, USP24, USP25, USP26, USP27X, USP28, USP29, USP3, USP30, USP31,USP32, USP33, USP34, USP35, USP36, USP37, USP38, USP39, USP4, USP40,USP41, USP42, USP43, USP44, USP45, USP46, USP47, USP48, USP49, USP5,USP50, USP51, USP53, USP54, USP6, USP6NL, USP7, USP8, USP9X, USP9Y,USPL1, UST, UTF1, UTP11, UTP14A, UTP14C, UTP15, UTP18, UTP20, UTP23,UTP3, UTP4, UTP6, UTRN, UTS2, UTS2B, UTS2R, UTY, UVRAG, UVSSA, UXS1,UXT, VAC14, VAMP1, VAMP2, VAMP3, VAMP4, VAMP5, VAMP7, VAMP8, VANGL1,VANGL2, VAPA, VAPB, VARS, VARS2, VASH1, VASH2, VASN, VASP, VAT1, VAT1L,VAV1, VAV2, VAV3, VAX1, VAX2, VBP1, VCAM1, VCAN, VCL, VCP, VCPIP1,VCPKMT, VCX, VCX2, VCX3A, VCX3B, VCY, VCY1B, VDAC1, VDAC2, VDAC3, VDR,VEGFA, VEGFB, VEGFC, VEGFD, VENTX, VEPH1, VEZF1, VEZT, VGF, VGLL1,VGLL2, VGLL3, VGLL4, VHL, VHLL, VIL1, VILL, VIM, VIP, VIPAS39, VIPR1,VIPR2, VIRMA, VIT, VKORC1, VKORC1L1, VLDLR, VMA21, VMAC, VMO1, VMP1,VN1R1, VN1R2, VN1R4, VN1R5, VNN1, VNN2, VNN3, VOPP1, VPREB1, VPREB3,VPS11, VPS13A, VPS13B, VPS13C, VPS13D, VPS16, VPS18, VPS25, VPS26A,VPS26B, VPS28, VPS29, VPS33A, VPS33B, VPS35, VPS36, VPS37A, VPS37B,VPS37C, VPS37D, VPS39, VPS41, VPS45, VPS4A, VPS4B, VPS50, VPS51, VPS52,VPS53, VPS54, VPS72, VPS8, VPS9D1, VRK1, VRK2, VRK3, VRTN, VSIG1,VSIG10, VSIG10L, VSIG10L2, VSIG2, VSIG4, VSIG8, VSIR, VSNL1, VSTM1,VSTM2A, VSTM2B, VSTM2L, VSTM4, VSTM5, VSX1, VSX2, VTA1, VTCN1, VTI1A,VTI1B, VTN, VWA1, VWA2, VWA3A, VWA3B, VWA5A, VWA5B1, VWA5B2, VWA7, VWA8,VWC2, VWC2L, VWCE, VWDE, VWF, WAC, WAPL, WARS, WARS2, WAS, WASF1, WASF2,WASF3, WASHC1, WASHC2A, WASHC2C, WASHC3, WASHC4, WASHC5, WASL, WBP1,WBP11, WBP1L, WBP2, WBP2NL, WBP4, WDCP, WDFY1, WDFY2, WDFY3, WDFY4,WDHD1, WDPCP, WDR1, WDR11, WDR12, WDR13, WDR17, WDR18, WDR19, WDR20,WDR24, WDR25, WDR26, WDR27, WDR3, WDR31, WDR33, WDR34, WDR35, WDR36,WDR37, WDR38, WDR4, WDR41, WDR43, WDR44, WDR45, WDR45B, WDR46, WDR47,WDR48, WDR49, WDR5, WDR53, WDR54, WDR55, WDR59, WDR5B, WDR6, WDR60,WDR61, WDR62, WDR63, WDR64, WDR66, WDR7, WDR70, WDR72, WDR73, WDR74,WDR75, WDR76, WDR77, WDR78, WDR81, WDR82, WDR83, WDR83OS, WDR86, WDR87,WDR88, WDR89, WDR90, WDR91, WDR92, WDR93, WDR97, WDSUB1, WDTC1, WDYHV1,WEE1, WEE2, WFDC1, WFDC10A, WFDC10B, WFDC11, WFDC12, WFDC13, WFDC2,WFDC3, WFDC5, WFDC6, WFDC8, WFDC9, WFIKKN1, WFIKKN2, WFS1, WHAMM, WHRN,WIF1, WIPF1, WIPF2, WIPF3, WIPI1, WIPI2, WISP1, WISP2, WISP3, WIZ, WLS,WNK1, WNK2, WNK3, WNK4, WNT1, WNT10A, WNT10B, WNT11, WNT16, WNT2, WNT2B,WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B,WNT9A, WNT9B, WRAP53, WRAP73, WRB, WRN, WRNIP1, WSB1, WSB2, WSCD1,WSCD2, WT1, WTAP, WTH3DI, WTIP, WWC1, WWC2, WWC3, WWOX, WWP1, WWP2,WWTR1, XAB2, XAF1, XAGE1A, XAGE1B, XAGE2, XAGE3, XAGE5, XBP1, XCL1,XCL2, XCR1, XDH, XG, XIAP, XIRP1, XIRP2, XK, XKR3, XKR4, XKR5, XKR6,XKR7, XKR8, XKR9, XKRX, XPA, XPC, XPNPEP1, XPNPEP2, XPNPEP3, XPO1, XPO4,XPO5, XPO6, XPO7, XPOT, XPR1, XRCC1, XRCC2, XRCC3, XRCC4, XRCC5, XRCC6,XRN1, XRN2, XRRA1, XXYLT1, XYLB, XYLT1, XYLT2, YAE1D1, YAF2, YAP1, YARS,YARS2, YBEY, YBX1, YBX2, YBX3, YDJC, YEATS2, YEATS4, YES1, YIF1A, YIF1B,YIPF1, YIPF2, YIPF3, YIPF4, YIPF5, YIPF6, YIPF7, YJEFN3, YKT6, YLPM1,YME1L1, YOD1, YPEL1, YPEL2, YPEL3, YPEL4, YPEL5, YRDC, YTHDC1, YTHDC2,YTHDF1, YTHDF2, YTHDF3, YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ, YWHAZ, YY1,YY1AP1, YY2, Z82206.1, Z83844.1, Z84492.1, Z98749.3, Z98752.3, ZACN,ZADH2, ZAN, ZAP70, ZAR1, ZAR1L, ZBBX, ZBED1, ZBED2, ZBED3, ZBED4, ZBED5,ZBED6, ZBED6CL, ZBED8, ZBED9, ZBP1, ZBTB1, ZBTB10, ZBTB11, ZBTB12,ZBTB14, ZBTB16, ZBTB17, ZBTB18, ZBTB2, ZBTB20, ZBTB21, ZBTB22, ZBTB24,ZBTB25, ZBTB26, ZBTB3, ZBTB32, ZBTB33, ZBTB34, ZBTB37, ZBTB38, ZBTB39,ZBTB4, ZBTB40, ZBTB41, ZBTB42, ZBTB43, ZBTB44, ZBTB45, ZBTB46, ZBTB47,ZBTB48, ZBTB49, ZBTB5, ZBTB6, ZBTB7A, ZBTB7B, ZBTB7C, ZBTB8A, ZBTB8B,ZBTB8OS, ZBTB9, ZC2HC1A, ZC2HC1B, ZC2HC1C, ZC3H10, ZC3H11A, ZC3H11B,ZC3H12A, ZC3H12B, ZC3H12C, ZC3H12D, ZC3H13, ZC3H14, ZC3H15, ZC3H18,ZC3H3, ZC3H4, ZC3H6, ZC3H7A, ZC3H7B, ZC3H8, ZC3HAV1, ZC3HAV1L, ZC3HC1,ZC4H2, ZCCHC10, ZCCHC11, ZCCHC12, ZCCHC13, ZCCHC14, ZCCHC17, ZCCHC18,ZCCHC2, ZCCHC24, ZCCHC3, ZCCHC4, ZCCHC6, ZCCHC7, ZCCHC8, ZCCHC9, ZCRB1,ZCWPW1, ZCWPW2, ZDBF2, ZDHHC1, ZDHHC11, ZDHHC11B, ZDHHC12, ZDHHC13,ZDHHC14, ZDHHC15, ZDHHC16, ZDHHC17, ZDHHC18, ZDHHC19, ZDHHC2, ZDHHC20,ZDHHC21, ZDHHC22, ZDHHC23, ZDHHC24, ZDHHC3, ZDHHC4, ZDHHC5, ZDHHC6,ZDHHC7, ZDHHC8, ZDHHC9, ZEB1, ZEB2, ZER1, ZFAND1, ZFAND2A, ZFAND2B,ZFAND3, ZFAND4, ZFAND5, ZFAND6, ZFAT, ZFC3H1, ZFHX2, ZFHX3, ZFHX4, ZFP1,ZFP14, ZFP2, ZFP28, ZFP3, ZFP30, ZFP36, ZFP36L1, ZFP36L2, ZFP37, ZFP41,ZFP42, ZFP57, ZFP62, ZFP64, ZFP69, ZFP69B, ZFP82, ZFP90, ZFP91,ZFP91-CNTF, ZFP92, ZFPL1, ZFPM1, ZFPM2, ZFR, ZFR2, ZFX, ZFY, ZFYVE1,ZFYVE16, ZFYVE19, ZFYVE21, ZFYVE26, ZFYVE27, ZFYVE28, ZFYVE9, ZG16,ZG16B, ZGLP1, ZGPAT, ZGRF1, ZHX1, ZHX1-C8orf76, ZHX2, ZHX3, ZIC1, ZIC2,ZIC3, ZIC4, ZIC5, ZIK1, ZIM2, ZIM3, ZKSCAN1, ZKSCAN2, ZKSCAN3, ZKSCAN4,ZKSCAN5, ZKSCAN7, ZKSCAN8, ZMAT1, ZMAT2, ZMAT3, ZMAT4, ZMAT5, ZMIZ1,ZMIZ2, ZMPSTE24, ZMYM1, ZMYM2, ZMYM3, ZMYM4, ZMYM5, ZMYM6, ZMYND10,ZMYND11, ZMYND12, ZMYND15, ZMYND19, ZMYND8, ZNF10, ZNF100, ZNF101,ZNF106, ZNF107, ZNF112, ZNF114, ZNF117, ZNF12, ZNF121, ZNF124, ZNF131,ZNF132, ZNF133, ZNF134, ZNF135, ZNF136, ZNF138, ZNF14, ZNF140, ZNF141,ZNF142, ZNF143, ZNF146, ZNF148, ZNF154, ZNF155, ZNF157, ZNF16, ZNF160,ZNF165, ZNF169, ZNF17, ZNF174, ZNF175, ZNF177, ZNF18, ZNF180, ZNF181,ZNF182, ZNF184, ZNF185, ZNF189, ZNF19, ZNF195, ZNF197, ZNF2, ZNF20,ZNF200, ZNF202, ZNF205, ZNF207, ZNF208, ZNF211, ZNF212, ZNF213, ZNF214,ZNF215, ZNF217, ZNF219, ZNF22, ZNF221, ZNF222, ZNF223, ZNF224, ZNF225,ZNF226, ZNF227, ZNF229, ZNF23, ZNF230, ZNF232, ZNF233, ZNF234, ZNF235,ZNF236, ZNF239, ZNF24, ZNF248, ZNF25, ZNF250, ZNF251, ZNF253, ZNF254,ZNF256, ZNF257, ZNF26, ZNF260, ZNF263, ZNF264, ZNF266, ZNF267, ZNF268,ZNF273, ZNF274, ZNF275, ZNF276, ZNF277, ZNF28, ZNF280A, ZNF280B,ZNF280C, ZNF280D, ZNF281, ZNF282, ZNF283, ZNF284, ZNF285, ZNF286A,ZNF286B, ZNF287, ZNF292, ZNF296, ZNF3, ZNF30, ZNF300, ZNF302, ZNF304,ZNF311, ZNF316, ZNF317, ZNF318, ZNF319, ZNF32, ZNF320, ZNF322, ZNF324,ZNF324B, ZNF326, ZNF329, ZNF330, ZNF331, ZNF333, ZNF334, ZNF335, ZNF337,ZNF33A, ZNF33B, ZNF34, ZNF341, ZNF343, ZNF345, ZNF346, ZNF347, ZNF35,ZNF350, ZNF354A, ZNF354B, ZNF354C, ZNF358, ZNF362, ZNF365, ZNF366,ZNF367, ZNF37A, ZNF382, ZNF383, ZNF384, ZNF385A, ZNF385B, ZNF385C,ZNF385D, ZNF391, ZNF394, ZNF395, ZNF396, ZNF397, ZNF398, ZNF404, ZNF407,ZNF408, ZNF41, ZNF410, ZNF414, ZNF415, ZNF416, ZNF417, ZNF418, ZNF419,ZNF420, ZNF423, ZNF425, ZNF426, ZNF428, ZNF429, ZNF43, ZNF430, ZNF431,ZNF432, ZNF433, ZNF436, ZNF438, ZNF439, ZNF44, ZNF440, ZNF441, ZNF442,ZNF443, ZNF444, ZNF445, ZNF446, ZNF449, ZNF45, ZNF451, ZNF454, ZNF460,ZNF461, ZNF462, ZNF467, ZNF468, ZNF469, ZNF470, ZNF471, ZNF473, ZNF474,ZNF479, ZNF48, ZNF480, ZNF483, ZNF484, ZNF485, ZNF486, ZNF487, ZNF488,ZNF490, ZNF491, ZNF492, ZNF493, ZNF496, ZNF497, ZNF500, ZNF501, ZNF502,ZNF503, ZNF506, ZNF507, ZNF510, ZNF511, ZNF512, ZNF512B, ZNF513, ZNF514,ZNF516, ZNF517, ZNF518A, ZNF518B, ZNF519, ZNF521, ZNF524, ZNF525,ZNF526, ZNF527, ZNF528, ZNF529, ZNF530, ZNF532, ZNF534, ZNF536, ZNF540,ZNF541, ZNF543, ZNF544, ZNF546, ZNF547, ZNF548, ZNF549, ZNF550, ZNF551,ZNF552, ZNF554, ZNF555, ZNF556, ZNF557, ZNF558, ZNF559, ZNF559-ZNF177,ZNF560, ZNF561, ZNF562, ZNF563, ZNF564, ZNF565, ZNF566, ZNF567, ZNF568,ZNF569, ZNF57, ZNF570, ZNF571, ZNF572, ZNF573, ZNF574, ZNF575, ZNF576,ZNF577, ZNF578, ZNF579, ZNF580, ZNF581, ZNF582, ZNF583, ZNF584, ZNF585A,ZNF585B, ZNF586, ZNF587, ZNF587B, ZNF589, ZNF592, ZNF593, ZNF594,ZNF595, ZNF596, ZNF597, ZNF598, ZNF599, ZNF600, ZNF605, ZNF606, ZNF607,ZNF608, ZNF609, ZNF610, ZNF611, ZNF613, ZNF614, ZNF615, ZNF616, ZNF618,ZNF619, ZNF620, ZNF621, ZNF622, ZNF623, ZNF624, ZNF625, ZNF625-ZNF20,ZNF626, ZNF627, ZNF628, ZNF629, ZNF630, ZNF638, ZNF639, ZNF641, ZNF644,ZNF645, ZNF646, ZNF648, ZNF649, ZNF652, ZNF653, ZNF654, ZNF655, ZNF658,ZNF66, ZNF660, ZNF662, ZNF664, ZNF665, ZNF667, ZNF668, ZNF669, ZNF670,ZNF670-ZNF695, ZNF671, ZNF672, ZNF674, ZNF675, ZNF676, ZNF677, ZNF678,ZNF679, ZNF680, ZNF681, ZNF682, ZNF683, ZNF684, ZNF687, ZNF688, ZNF689,ZNF69, ZNF691, ZNF692, ZNF695, ZNF696, ZNF697, ZNF699, ZNF7, ZNF70,ZNF700, ZNF701, ZNF703, ZNF704, ZNF705A, ZNF705B, ZNF705D, ZNF705E,ZNF705G, ZNF706, ZNF707, ZNF708, ZNF709, ZNF71, ZNF710, ZNF711, ZNF713,ZNF714, ZNF716, ZNF717, ZNF718, ZNF720, ZNF721, ZNF724, ZNF726, ZNF727,ZNF728, ZNF729, ZNF730, ZNF732, ZNF735, ZNF736, ZNF737, ZNF738, ZNF74,ZNF740, ZNF746, ZNF747, ZNF749, ZNF750, ZNF75A, ZNF75D, ZNF76, ZNF761,ZNF763, ZNF764, ZNF765, ZNF766, ZNF768, ZNF77, ZNF770, ZNF771, ZNF772,ZNF773, ZNF774, ZNF775, ZNF776, ZNF777, ZNF778, ZNF780A, ZNF780B,ZNF781, ZNF782, ZNF783, ZNF784, ZNF785, ZNF786, ZNF787, ZNF788, ZNF789,ZNF79, ZNF790, ZNF791, ZNF792, ZNF793, ZNF799, ZNF8, ZNF80, ZNF800,ZNF804A, ZNF804B, ZNF805, ZNF808, ZNF81, ZNF813, ZNF814, ZNF816,ZNF816-ZNF321P, ZNF821, ZNF823, ZNF827, ZNF829, ZNF83, ZNF830, ZNF831,ZNF835, ZNF836, ZNF837, ZNF839, ZNF84, ZNF841, ZNF843, ZNF844, ZNF845,ZNF846, ZNF85, ZNF850, ZNF852, ZNF853, ZNF860, ZNF862, ZNF865, ZNF878,ZNF879, ZNF880, ZNF883, ZNF888, ZNF891, ZNF90, ZNF91, ZNF92, ZNF93,ZNF98, ZNF99, ZNFX1, ZNHIT1, ZNHIT2, ZNHIT3, ZNHIT6, ZNRD1, ZNRF1,ZNRF2, ZNRF3, ZNRF4, ZP1, ZP2, ZP3, ZP4, ZPBP, ZPBP2, ZPLD1, ZPR1,ZRANB1, ZRANB2, ZRANB3, ZRSR1, ZRSR2, ZSCAN1, ZSCAN10, ZSCAN12, ZSCAN16,ZSCAN18, ZSCAN2, ZSCAN20, ZSCAN21, ZSCAN22, ZSCAN23, ZSCAN25, ZSCAN26,ZSCAN29, ZSCAN30, ZSCAN31, ZSCAN32, ZSCAN4, ZSCAN5A, ZSCAN5B, ZSCAN5C,ZSCAN9, ZSWIM1, ZSWIM2, ZSWIM3, ZSWIM4, ZSWIM5, ZSWIM6, ZSWIM7, ZSWIM8,ZUFSP, ZW10, ZWILCH, ZWINT, ZXDA, ZXDB, ZXDC, ZYG11A, ZYG11B, ZYX,ZZEF1, and ZZZ3.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of an autoimmune disorder, an inflammatory disorder, or aproliferative disorder, or a disorder commonly occurring in connectionwith transplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

One or more other therapeutic agent may be administered separately froma compound or composition of the invention, as part of a multiple dosageregimen. Alternatively, one or more other therapeutic agents may be partof a single dosage form, mixed together with a compound of thisinvention in a single composition. If administered as a multiple dosageregime, one or more other therapeutic agent and a compound orcomposition of the invention may be administered simultaneously,sequentially or within a period of time from one another, for examplewithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments,one or more other therapeutic agent and a compound or composition of theinvention are administered as a multiple dosage regimen within greaterthan 24 hours apart.

In one embodiment, the present invention provides a compositioncomprising a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents. The therapeuticagent may be administered together with a provided compound or apharmaceutically acceptable salt thereof, or may be administered priorto or following administration of a provided compound or apharmaceutically acceptable salt thereof. Suitable therapeutic agentsare described in further detail below. In certain embodiments, aprovided compound or a pharmaceutically acceptable salt thereof may beadministered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16hours, 17 hours, or 18 hours before the therapeutic agent. In otherembodiments, a provided compound or a pharmaceutically acceptable saltthereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours,8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agents.Such additional therapeutic agents may be small molecules or recombinantbiologic agents and include, for example, acetaminophen, non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroidssuch as prednisone, prednisolone, methylprednisolone, hydrocortisone,and the like, probenecid, allopurinol, febuxostat (Uloric®),sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), goldsalts such as gold thioglucose (Solganal®), gold thiomalate(Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® orCuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®),chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide(Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab(Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) andadalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) andrilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors suchas tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating gout comprising administering to a patient in need thereof aprovided compound or a pharmaceutically acceptable salt thereof and oneor more additional therapeutic agents selected from non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroidssuch as prednisone, prednisolone, methylprednisolone, hydrocortisone,and the like, probenecid, allopurinol and febuxostat (Uloric®).

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected fromnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroidssuch as prednisone, prednisolone, methylprednisolone, hydrocortisone,and the like, sulfasalazine (Azulfidine®), antimalarials such ashydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate(Rheumatrex®), gold salts such as gold thioglucose (Solganal®), goldthiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine(Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide(Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®),leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®),infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol(Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra(Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab(Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®) and“anti-IL-6” agents such as tocilizumab (Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof aprovided compound or a pharmaceutically acceptable salt thereof and oneor more additional therapeutic agents selected from acetaminophen,non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac,cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonalantibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatinglupus comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from acetaminophen, non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone,prednisolone, methylprednisolone, hydrocortisone, and the like,antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®),azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine®or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatinginflammatory bowel disease comprising administering to a patient in needthereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected frommesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such asdiphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid bindingagents such as cholestyramine, alosetron (Lotronex®), lubiprostone(Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol(MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics orantispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies,steroids, and antibiotics such as Flagyl or ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from Singulair®, beta-2 agonistssuch as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol(Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®),terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) andformoterol (Foradil®), anticholinergic agents such as ipratropiumbromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroidssuch as prednisone, prednisolone, beclomethasone dipropionate(Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®),mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide(Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®,Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such asomalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from beta-2 agonists such asalbuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®),metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutalinesulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol(Foradil®), anticholinergic agents such as ipratropium bromide(Atrovent®) and tiotropium (Spiriva®), methylxanthines such astheophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) andaminophylline, inhaled corticosteroids such as prednisone, prednisolone,beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®),triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide(Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®,

In some embodiments, the present invention provides a method of treatingHIV comprising administering to a patient in need thereof a providedcompound or a pharmaceutically acceptable salt thereof and one or moreadditional therapeutic agents selected from nucleoside reversetranscriptase inhibitors such as zidovudine (Retrovir®), abacavir(Ziagen®), abacavir/lamivudine (Epzicom®),abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®),emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine(Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®),non-nucleoside reverse transcriptase inhibitors such as delavirdine(Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) andetravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agentsselected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinationsthereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected fromrituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehogsignaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and a Hedgehog (Hh) signaling pathway inhibitor.In some embodiments, the hematological malignancy is DLBCL (Ramirez etal “Defining causative factors contributing in the activation ofhedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012),published online July 17, and incorporated herein by reference in itsentirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agentsselected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected frombortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehogsignaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2inhibitor, a PI3K inhibitor, a SYK inhibitor in combination withlenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating Waldenstrom's macroglobulinemia comprising administering to apatient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agentsselected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®,Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab(Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYKinhibitor.

In some embodiments, one or more other therapeutic agent is anantagonist of the hedgehog pathway. Approved hedgehog pathway inhibitorswhich may be used in the present invention include sonidegib (Odomzo®,Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both fortreatment of basal cell carcinoma.

In some embodiments, one or more other therapeutic agent is a Poly ADPribose polymerase (PARP) inhibitor. In some embodiments, a PARPinhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib(Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib(MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib(ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

In some embodiments, one or more other therapeutic agent is a histonedeacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor isselected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®,Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®,Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals)(NCT00866333); and chidamide (Epidaza®, HBI-8000, ChipscreenBiosciences, China).

In some embodiments, one or more other therapeutic agent is a CDKinhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib(Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); andtrilaciclib (G1T28, G1 Therapeutics).

In some embodiments, one or more other therapeutic agent is a folic acidinhibitor. Approved folic acid inhibitors useful in the presentinvention include pemetrexed (Alimta®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is a CCchemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studiedthat may be useful in the present invention include mogamulizumab(Poteligeo®, Kyowa Hakko Kirin, Japan).

In some embodiments, one or more other therapeutic agent is anisocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studiedwhich may be used in the present invention include AG120 (Celgene;NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032(Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, one or more other therapeutic agent is an arginaseinhibitor. Arginase inhibitors being studied which may be used in thepresent invention include AEB1102 (pegylated recombinant arginase,Aeglea Biotherapeutics), which is being studied in Phase 1 clinicaltrials for acute myeloid leukemia and myelodysplastic syndrome(NCT02732184) and solid tumors (NCT02561234); and CB-1158 (CalitheraBiosciences).

In some embodiments, one or more other therapeutic agent is aglutaminase inhibitor. Glutaminase inhibitors being studied which may beused in the present invention include CB-839 (Calithera Biosciences).

In some embodiments, one or more other therapeutic agent is an antibodythat binds to tumor antigens, that is, proteins expressed on the cellsurface of tumor cells. Approved antibodies that bind to tumor antigenswhich may be used in the present invention include rituximab (Rituxan®,Genentech/BiogenIdec); ofatumumab (anti-CD20, Arzerra®,GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech),ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, SpectrumPharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech),dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics);trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumabemtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); andpertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin(anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

In some embodiments, one or more other therapeutic agent is atopoisomerase inhibitor. Approved topoisomerase inhibitors useful in thepresent invention include irinotecan (Onivyde®, MerrimackPharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomeraseinhibitors being studied which may be used in the present inventioninclude pixantrone (Pixuvri®, CTI Biopharma).

In some embodiments, one or more other therapeutic agent is an inhibitorof anti-apoptotic proteins, such as BCL-2. Approved anti-apoptoticswhich may be used in the present invention include venetoclax(Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen).Other therapeutic agents targeting apoptotic proteins which haveundergone clinical testing and may be used in the present inventioninclude navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, one or more other therapeutic agent is an androgenreceptor inhibitor. Approved androgen receptor inhibitors useful in thepresent invention include enzalutamide (Xtandi®, Astellas/Medivation);approved inhibitors of androgen synthesis include abiraterone (Zytiga®,Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone(GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).

In some embodiments, one or more other therapeutic agent is a selectiveestrogen receptor modulator (SERM), which interferes with the synthesisor activity of estrogens. Approved SERMs useful in the present inventioninclude raloxifene (Evista®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is an inhibitorof bone resorption. An approved therapeutic which inhibits boneresorption is Denosumab (Xgeva®, Amgen), an antibody that binds toRANKL, prevents binding to its receptor RANK, found on the surface ofosteoclasts, their precursors, and osteoclast-like giant cells, whichmediates bone pathology in solid tumors with osseous metastases. Otherapproved therapeutics that inhibit bone resorption includebisphosphonates, such as zoledronic acid (Zometa®, Novartis).

In some embodiments, one or more other therapeutic agent is an inhibitorof interaction between the two primary p53 suppressor proteins, MDMX andMDM2. Inhibitors of p53 suppression proteins being studied which may beused in the present invention include ALRN-6924 (Aileron), a stapledpeptide that equipotently binds to and disrupts the interaction of MDMXand MDM2 with p53. ALRN-6924 is currently being evaluated in clinicaltrials for the treatment of AML, advanced myelodysplastic syndrome (MDS)and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, one or more other therapeutic agent is an inhibitorof transforming growth factor-beta (TGF-beta or TGFß). Inhibitors ofTGF-beta proteins being studied which may be used in the presentinvention include NIS793 (Novartis), an anti-TGF-beta antibody beingtested in the clinic for treatment of various cancers, including breast,lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer(NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteinsis fresolimumab (GC1008; Sanofi-Genzyme), which is being studied formelanoma (NCT00923169); renal cell carcinoma (NCT00356460); andnon-small cell lung cancer (NCT02581787). Additionally, in someembodiments, the additional therapeutic agent is a TGF-beta trap, suchas described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials fortreatment of solid tumors is M7824 (Merck KgaA—formerly MSB0011459X),which is a bispecific, anti-PD-L1/TGFß trap compound (NCT02699515); and(NCT02517398). M7824 is comprised of a fully human IgGI antibody againstPD-L1 fused to the extracellular domain of human TGF-beta receptor II,which functions as a TGFß “trap.”

In some embodiments, one or more other therapeutic agent is selectedfrom glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), ananti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxicMMAE. gpNMB is a protein overexpressed by multiple tumor typesassociated with cancer cells' ability to metastasize.

In some embodiments, one or more other therapeutic agent is anantiproliferative compound. Such antiproliferative compounds include,but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive compounds; alkylating compounds; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; matrix metalloproteinase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies; compounds which target, decreaseor inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (Temodal®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayBioPharma, AZd₆244 from AstraZeneca, PD181461 from Pfizer andleucovorin.

In some embodiments, the present invention provides a method of treatingAlzheimer's disease comprising administering to a patient in needthereof a provided compound or a pharmaceutically acceptable saltthereof and one or more additional therapeutic agents selected fromdonepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®),tacrine (Cognex®), and memantine (Namenda®).

In some embodiments, one or more other therapeutic agent is a taxanecompound, which causes disruption of microtubules, which are essentialfor cell division. In some embodiments, a taxane compound is selectedfrom paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®,Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel(Abraxane®; Abraxis/Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis),and SID530 (SK Chemicals, Co.) (NCT00931008).

In some embodiments, one or more other therapeutic agent is a nucleosideinhibitor, or a therapeutic agent that interferes with normal DNAsynthesis, protein synthesis, cell replication, or will otherwiseinhibit rapidly proliferating cells.

In some embodiments, a nucleoside inhibitor is selected from trabectedin(guanidine alkylating agent, Yondelis®, Janssen Oncology),mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals);vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals;Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®,Merck); cytarabine injection (ara-C, antimetabolic cytidine analog,Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb;Gleostine®, NextSource Biotechnology); azacitidine (pyrimidinenucleoside analog of cytidine, Vidaza®, Celgene); omacetaxinemepesuccinate (cephalotaxine ester) (protein synthesis inhibitor,Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi(enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSAPharma); eribulin mesylate (microtubule inhibitor, tubulin-basedantimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor,tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine(thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine(bifunctional mechlorethamine derivative, believed to form interstrandDNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-syntheticanalog of epothilone B, microtubule inhibitor, tubulin-basedantimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug ofdeoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®,Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor,competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); andtrifluridine and tipiracil (thymidine-based nucleoside analog andthymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

In some embodiments, one or more other therapeutic agent is a kinaseinhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinaseinhibitors useful in the present invention include: bevacizumab(Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody;ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody andziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi).VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib(Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib(Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AGand Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®,Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®,Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abltyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis);nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®,BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib(Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such asgefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®,Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib(Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activatedEGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, AriadPharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib(Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib(Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, suchas crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); andalectinib (Alecenza®, Genentech/Roche); Bruton's tyrosine kinaseinhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); andFlt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

Other kinase inhibitors and VEGF-R antagonists that are in developmentand may be used in the present invention include tivozanib (AveoPharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (ClovisOncology); dovitinib (TK1258, Novartis); Chiauanib (ChipscreenBiosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories);neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511,Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, IncyteCorporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib(Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib(Amgen/Takeda).

In another embodiment, the present invention provides a method oftreating organ transplant rejection or graft vs. host disease comprisingadministering to a patient in need thereof a provided compound or apharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents selected from a steroid, cyclosporin, FK506,rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYKinhibitor.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and a BTK inhibitor, wherein the disease isselected from inflammatory bowel disease, arthritis, systemic lupuserythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura(ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis,Still's disease, juvenile arthritis, diabetes, myasthenia gravis,Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmunethyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis,Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylosis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia,celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenicpurpura, optic neuritis, scleroderma, primary biliary cirrhosis,Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,membranous glomerulonephropathy, endometriosis, interstitial cystitis,pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma,vulvodynia, a hyperproliferative disease, rejection of transplantedorgans or tissues, Acquired Immunodeficiency Syndrome (AIDS, also knownas HIV), type 1 diabetes, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis, asthma,appendicitis, atopic dermatitis, asthma, allergy, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn'sdisease, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitissuppurativa, immunoglobulin A nephropathy, interstitial lung disease,laryngitis, mastitis, meningitis, myelitis myocarditis, myositis,nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis,parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, polymyositis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis,vasculitis, or vulvitis, B-cell proliferative disorder, e.g., diffuselarge B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia,B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrommacroglobulinemia, splenic marginal zone lymphoma, multiple myeloma(also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin'slymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodalmarginal zone B cell lymphoma, mantle cell lymphoma, mediastinal(thymic) large B cell lymphoma, intravascular large B cell lymphoma,primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoidgranulomatosis, breast cancer, prostate cancer, or cancer of the mastcells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma,systemic mastocytosis), bone cancer, colorectal cancer, pancreaticcancer, diseases of the bone and joints including, without limitation,rheumatoid arthritis, seronegative spondyloarthropathies (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis,bone cancer, bone metastasis, a thromboembolic disorder, (e.g.,myocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, deep venousthrombosis), inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,psoriatic arthritis, juvenile arthritis, osteoarthritis, chronicidiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia,myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis,degenerative joint disease, vitiligo, autoimmune hypopituitarism,Guillain-Barre syndrome, Behcet's disease, scleroderma, mycosisfungoides, acute inflammatory responses (such as acute respiratorydistress syndrome and ischemia/reperfusion injury), and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and a PI3K inhibitor, wherein the disease isselected from a cancer, a neurodegenerative disorder, an angiogenicdisorder, a viral disease, an autoimmune disease, an inflammatorydisorder, a hormone-related disease, conditions associated with organtransplantation, immunodeficiency disorders, a destructive bonedisorder, a proliferative disorder, an infectious disease, a conditionassociated with cell death, thrombin-induced platelet aggregation,chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL),liver disease, pathologic immune conditions involving T cell activation,a cardiovascular disorder, and a CNS disorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a provided compound or a pharmaceuticallyacceptable salt thereof and a PI3K inhibitor, wherein the disease isselected from benign or malignant tumor, carcinoma or solid tumor of thebrain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland,bladder, breast, stomach, gastric tumors, ovaries, colon, rectum,prostate, pancreas, lung, vagina, endometrium, cervix, testis,genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma,glioblastomas, neuroblastomas, multiple myeloma or gastrointestinalcancer, especially colon carcinoma or colorectal adenoma or a tumor ofthe neck and head, an epidermal hyperproliferation, psoriasis, prostatehyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma,adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cellcarcinoma, non-small-cell lung carcinoma, lymphomas, (including, forexample, non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (alsotermed Hodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments, one or more other therapeutic agent is aphosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, aPI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib(BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib(GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib(formerly IPI-145, Infinity Pharmaceuticals); PQR309 (PiqurTherapeutics, Switzerland); and TGR1202 (formerly RP5230, TGTherapeutics).

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer, an autoimmune disorder, a proliferative disorder, aninflammatory disorder, a neurodegenerative or neurological disorder,schizophrenia, a bone-related disorder, liver disease, or a cardiacdisorder. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. Compounds of the invention are preferablyformulated in dosage unit form for ease of administration and uniformityof dosage. The expression “dosage unit form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity or degrading a protein kinase in abiological sample comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

According to another embodiment, the invention relates to a method ofinhibiting or degrading IRAK-1, IRAK-2, and/or IRAK-4, or a mutantthereof, activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition and/or degradation of a protein kinase, or a protein kinaseselected from IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof,activity in a biological sample is useful for a variety of purposes thatare known to one of skill in the art. Examples of such purposes include,but are not limited to, blood transfusion, organ-transplantation,biological specimen storage, and biological assays.

Another embodiment of the present invention relates to a method ofdegrading a protein kinase and/or inhibiting protein kinase activity ina patient comprising the step of administering to said patient acompound of the present invention, or a composition comprising saidcompound.

According to another embodiment, the invention relates to a method ofdegrading and/or inhibiting one or more of IRAK-1, IRAK-2, and/orIRAK-4, or a mutant thereof, activity in a patient comprising the stepof administering to said patient a compound of the present invention, ora composition comprising said compound. In other embodiments, thepresent invention provides a method for treating a disorder mediated byone or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, in apatient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits estrogen production, for instance, the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane is marketed under thetrade name Aromasin™. Formestane is marketed under the trade nameLentaron™. Fadrozole is marketed under the trade name Afema™.Anastrozole is marketed under the trade name Arimidex™ Letrozole ismarketed under the trade names Femara™ or Femar™. Aminoglutethimide ismarketed under the trade name Orimeten™. A combination of the inventioncomprising a chemotherapeutic agent which is an aromatase inhibitor isparticularly useful for the treatment of hormone receptor positivetumors, such as breast tumors.

In some embodiments, one or more other therapeutic agent is an mTORinhibitor, which inhibits cell proliferation, angiogenesis and glucoseuptake. In some embodiments, an mTOR inhibitor is everolimus (Afinitor®,Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®,Pfizer).

In some embodiments, one or more other therapeutic agent is an aromataseinhibitor. In some embodiments, an aromatase inhibitor is selected fromexemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) andletrozole (Femara®, Novartis).

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™ Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO 2008/118802, US 2010/0197686), navitoclax(and analogs thereof, see U.S. Pat. No. 7,390,799), NH-1 (ShenayngPharmaceutical University), obatoclax (and analogs thereof, see WO2004/106328, US 2005/0014802), 5-001 (Gloria Pharmaceuticals), TW seriescompounds (Univ. of Michigan), and venetoclax. In some embodiments theBcl-2 inhibitor is a small molecule therapeutic. In some embodiments theBcl-2 inhibitor is a peptidomimetic.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aP13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); l) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, C1-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

In some embodiments, one or more other therapeutic agent is a growthfactor antagonist, such as an antagonist of platelet-derived growthfactor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).Approved PDGF antagonists which may be used in the present inventioninclude olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonistswhich may be used in the present invention include cetuximab (Erbitux®,Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®,Amgen); and osimertinib (targeting activated EGFR, Tagrisso®,AstraZeneca).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-0, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO 2008/039218, US 2008/0108636 and WO 2011/090760, US2010/0249092, the entirety of each of which is herein incorporated byreference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO 2003/063794, US 2004/0029902, WO 2005/007623, US2005/0075306, and WO 2006/078846, US 2006/0211657, the entirety of eachof which is herein incorporated by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO 2004/019973, US 2004/0106569, WO 2004/089925, US2004/0242631, U.S. Pat. No. 8,138,347, WO 2002/088112, US 2004/0116421,WO 2007/084786, US 2010/0249126, WO 2007/129161, US 2008/0076768, WO2006/122806, US 2008/0194579, WO 2005/113554, US 2008/0275067, and WO2007/044729, US 2010/0087440, the entirety of each of which is hereinincorporated by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO 2009/114512, US 2009/0233903, WO 2008/109943, US2010/0197671, WO 2007/053452, US 2007/0191405, WO 2001/0142246, US2001/0053782, and WO 2007/070514, US 2007/0135461, the entirety of eachof which is herein incorporated by reference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™), carfilzomib(Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda), and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PR064553 (anti-CD40) and2C₄ Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene),VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2aagonists; A2b antagonists; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 pg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of one or more other therapeutic agent present in thecompositions of this invention may be no more than the amount that wouldnormally be administered in a composition comprising that therapeuticagent as the only active agent. Preferably the amount of one or moreother therapeutic agent in the presently disclosed compositions willrange from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent. In some embodiments, one or more other therapeutic agent isadministered at a dosage of about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% ofthe amount normally administered for that agent. As used herein, thephrase “normally administered” means the amount an FDA approvedtherapeutic agent is approvided for dosing per the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fni4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTOR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTOR, Lymphotoxin α1β2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO 2011/070024, US 2011/0165156, WO 2011/0107553, US 2012/0329997, WO2011/131407, US 2013/0005949, WO 2013/087699, US 2014/0336363, WO2013/119716, WO 2013/132044, US 2014/0079706) or FPA-008 (WO2011/140249, US 2011/0274683; WO 2013/169264; WO 2014/036357, US2014/0079699).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634, US 2010/0203056), durvalumab (MEDI4736), BMS-936559 (WO2007/005874, US 2009/0055944), and MSB0010718C (WO 2013/079174, US2014/0341917).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO 2010/019570, US2010/0150892, WO 2014/008218, US 2014/0093511), or IMP-731 or IMP-321(WO 2008/132601, US 2010/0233183, WO 2009/044273, US 2011/0008331).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO2006/105021, US 2007/0098719, WO 2009/009116, US 2009/0136494), orMK-4166 (WO 2011/028683, US 2012/0189639).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO2009/073620, US 2011/0053941, WO 2009/132238, US 2011/0136796, WO2011/056652, US 2012/0277217, WO 2012/142237, US 2014/0066625).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO 2006/029879,U.S. Pat. No. 7,501,496).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO2011/109400, US 2013/0149236).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor-reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenolmebutate (Picato®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-1h68/GLV-1h153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682, the entirety of each of which isherein incorporated by reference, which discloses CAR-T cells engineeredto comprise an extracellular domain having an antigen binding domain(such as a domain that binds to CD19), fused to an intracellularsignaling domain of the T cell antigen receptor complex zeta chain (suchas CD3 zeta). When expressed in the T cell, the CAR is able to redirectantigen recognition based on the antigen binding specificity. In thecase of CD19, the antigen is expressed on malignant B cells. Over 200clinical trials are currently in progress employing CAR-T in a widerange of indications. [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that may be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescripted in Jerry L. Adams ET. AL., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by reference in itsentirety. In some embodiment, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams ET. AL. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncology target selected from those listed in Table 2 of Jerry L.Adams ET. AL. In some embodiments, an immuno-oncology agent is a smallmolecule agent selected from those listed in Table 2 of Jerry L. AdamsET. AL.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by reference in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the content of which is incorporated herein byreference in its entirety. In some embodiments, an immuno-oncology agentis a bispecific T cell engager (BiTE®) antibody construct. In someembodiments, a bispecific T cell engager (BiTE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodiments, abispecific T cell engager (BiTE®) antibody construct is an EGFR/CD3bispecific antibody construct. In some embodiments, a bispecific T cellengager (BiTE®) antibody construct activates T cells. In someembodiments, a bispecific T cell engager (BiTE®) antibody constructactivates T cells, which release cytokines inducing upregulation ofintercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.In some embodiments, a bispecific T cell engager (BiTE®) antibodyconstruct activates T cells which result in induced bystander celllysis. In some embodiments, the bystander cells are in solid tumors. Insome embodiments, the bystander cells being lysed are in proximity tothe BiTE®-activated T cells. In some embodiment, the bystander cellscomprises tumor-associated antigen (TAA) negative cancer cells. In someembodiment, the bystander cells comprise EGFR-negative cancer cells. Insome embodiments, an immuno-oncology agent is an antibody which blocksthe PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncologyagent is an ex-vivo expanded tumor-infiltrating T cell. In someembodiments, an immuno-oncology agent is a bispecific antibody constructor chimeric antigen receptors (CARs) that directly connect T cells withtumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, T6, and memory CD8⁺ (αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody),anti-OX40, PD-Ll monoclonal Antibody (Anti-B7-H1; MEDI4736), MK-3475(PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDlantibody), BY55 monoclonal antibody, AMP224 (anti-PDLI antibody),BMS-936559 (anti-PDLI antibody), MPLDL3280A (anti-PDLI antibody),MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpointinhibitor). Checkpoint protein ligands include, but are not limited toPD-Ll, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck);ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgG1 Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KTR) inhibitors. KTR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that may be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Example 1. Synthesis of 5-(1-oxoisoindolin-2-yl)thiazolidine-2,4-dione(I-59)

Step A: 5-(1-oxoisoindolin-2-yl)thiazolidine-2,4-dione (I-59). To amixture of isoindolin-1-one (266 mg, 2.0 mmol) in THE (5 mL) at 0° C.was added NaH (240 mg, 6 mmol) in portions and the mixture was stirredat 0° C. for 0.5 h. A solution of 5-bromothiazolidine-2,4-dione (1.57 g,8 mmol) in THE (8 mL) was added dropwise and stirred at 0° C. for 10min. To the mixture was added H₂O (50 mL) and the mixture was extractedwith EtOAc (50 mL×2). The combined organic layer was washed with brine(50 mL×3), dried over Na₂SO₄, filtered, and concentrated in vacuo andpurified via column chromatography (Petroleum ether/EtOAc=4/1) to givethe title compound (5.8 mg, 1.2% yield) as a white solid. ¹H NMR (400MHz, DMSO-d6) δ ppm: 12.47 (s, 1H), 7.75-7.73 (d, J=7.6 Hz, 1H),7.70-7.67 (m, 1H), 7.64-7.62 (d, J=7.6 Hz, 1H), 7.56-7.52 (t, J=7.4 Hz,1H), 6.81 (s, 1H), 4.65-4.61 (d, J=17.2 Hz, 1H), 4.52-4.48 (d, J=16.8Hz, 1H). LC-MS: Calculated exact mass=248.0; Found [M+H]⁺=248.1.

Example 2. Synthesis of5-(2-oxo-5-phenyloxazolidin-3-yl)thiazolidine-2,4-dione (I-50)

Step A: 5-((2-hydroxy-2-phenylethyl)amino)thiazolidine-2,4-dione (2). Toa solution of 5-bromothiazolidine-2,4-dione (4.2 g, 21.87 mmol) in DMF(N,N-dimethylformamide) (100 mL) was added 2-amino-1-phenylethanol (2.0g, 14.58 mmol) and TEA (2.21 g, 21.87 mmol) at r.t. The reaction mixturewas stirred at r.t. for 5 h. TLC (EtOAc/DCM=1/1; silica gel plate)showed complete consumption of the starting material after this time.The reaction mixture solvent was removed under reduced pressure. Theresidue was purified via reverse phase column chromatography (MeCN/H₂O)to give the title compound (1.71 g, 46.5% yield) as a yellow oil.

Step B: 5-(2-oxo-5-phenyloxazolidin-3-yl)thiazolidine-2,4-dione (I-50).To a solution of5-((2-hydroxy-2-phenylethyl)amino)thiazolidine-2,4-dione (1.3 g, 5.16mmol) in THE (30 mL) was added dropwise carbonyldiimidazole (CDI) (1.25g, 7.74 mmol) in THE (5 mL) at r.t. The reaction mixture was stirred atr.t. for another 12h. TLC (EtOAc/DCM=1/1; silica gel plate) showedcomplete consumption of the starting material after this time. Thereaction mixture solvent was removed under reduced pressure and theresidue was purified via reverse phase column chromatography (MeCN/H₂O)to give the title compound (201.1 mg, 14.01% yield) as a white solid. ¹HNMR (400 MHz, DMSO-d6) δ ppm: 12.45 (s, 2H), 7.51-7.35 (m, 10H), 6.55(d, J=4.3 Hz, 2H), 5.79-5.69 (m, 2H), 4.13 (t, J=8.8 Hz, 1H), 3.96 (t,J=8.7 Hz, 1H), 3.58 (dd, J=8.7, 7.4 Hz, 1H), 3.41 (dd, J=8.8, 6.7 Hz,1H). LC-MS: Calculated exact mass=278.04; Found [M+H]⁺=279.01.

Example 3. Synthesis of5-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-thiazolidine-2,4-dione(I-51)

Step A:5-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-thiazolidine-2,4-dione(I-51). To a solution of 1-methyl-1,3-dihydro-benzoimidazol-2-one (300mg, 1.13 mmol) in DMF (4.0 mL) was added NaH (60% in mineral oil, 101.7mg, 3.39 mmol) at 0° C. under nitrogen. The reaction mixture was stirredat 0° C. under N₂ for 30 minutes. Then 5-bromo-thiazolidine-2,4-dione(230 mg, 1.13 mmol) in DMF (1 mL) was added slowly. After stirring atr.t. for 10 minutes, the reaction was quenched with water (30 mL) andextracted with EtOAc (50 mL×3). The combined organic layer was washedwith brine and dried over Na₂SO₄. The mixture was filtered and thefiltrate solvent was removed under reduced pressure. The residue waspurified via silica gel column chromatography (Petroleum ether/EtOAc) togive the title compound (22 mg, 7.4% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 12.7 (s, 1H), 7.76-7.13 (m, 5H), 3.34 (s, 3H).LC-MS: Calculated exact mass=263.0; Found [M+H]⁺=263.9.

Example 4. Synthesis of ethyl1-(2,4-dioxothiazolidin-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate(I-29)

Step A: ethyl1-(2,4-dioxothiazolidin-5-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate(I-29). To a solution of ethyl 6-oxo-1,6-dihydropyridine-3-carboxylate(50 mg, 0.3 mmol) in dry THF (5 mL) was added 1M LiHMDS in THF (0.36 mL,0.36 mmol) dropwise at 0° C. After addition, the mixture was stirred at0° C. for 1 h, then 5-bromothiazolidine-2,4-dione (70.56 mg, 0.36 mmol)in THE was added, and the mixture was warmed to room temperature andstirred overnight. The mixture was poured into water (10 mL), extractedwith EtOAc (10 mL×2), the organic layers were discarded, and the liquidlayer was extracted with DCM/isopropanol (3/1, 10 mL×3), then thecombined organic layers were concentrated under reduced pressure. Theresidue was purified by prep HPLC to give the title compound (3.8 mg,4.5% yield) as a white solid. LC-MS: Calculated exact mass=282.0 Found[M+H]⁺=283.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.81 (br. s., 1H),8.18 (br. s., 1H), 7.96 (d, J=9.51 Hz, 1H), 6.66 (d, J=9.38 Hz, 1H),6.35 (br. s., 1H), 4.36 (q, J=6.67 Hz, 2H), 1.33-1.43 (m, 3H).

Example 5. Synthesis of 3-(phenylthio)piperidine-2,6-dione (I-4)

Step A: 3-(phenylthio)piperidine-2,6-dione (I-4). A mixture ofbenzenethiol (300 mg, 2.73 mmol), 3-bromopiperidine-2,6-dione (628 mg,3.27 mmol), and Cs₂CO₃ (1.3 g, 410 mmol) in DMF (20 mL) was stirred for1 h at rt. To the mixture was added H₂O (50 mL) and the mixture wasextracted with EtOAc (50 mL×2). The combined organic layer was washedwith brine (50 mL×3), dried over Na₂SO₄, filtered, concentrated in vacuoand purified by column chromatography (Petroleum ether/EtOAc=1/1) togive the title compound (400 mg, 66% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d6) δ ppm: 10.91 (s, 1H), 7.50-7.47 (m, 2H), 7.39-7.29(m, 3H), 4.33-4.30 (dd, J=4.8 Hz, J=8.4 Hz, 1H), 2.57-2.51 (m, 2H),2.23-2.19 (m, 1H), 1.96-1.91 (m, 1H). LC-MS: Calculated exactmass=221.1; Found [M+H]⁺=222.1.

Example 6. Synthesis of 3-(pyridin-2-ylthio)piperidine-2,6-dione (I-6)

Step A: 3-(pyridin-2-ylthio)piperidine-2,6-dione (I-6). To a solution ofpyridine-2-thiol (34.6 mg, 0.312 mmol) in DMF (3 mL) was added3-bromopiperidine-2,6-dione (100 mg, 0.467 mmol) and Cs₂CO₃ (152.3 mg,0.467 mmol) at r.t. The reaction mixture was stirred at r.t. for 1.5hour. TLC (Petroleum ether/EtOAc=1/1; silica gel plate) showed completeconsumption of the starting material after this time. The reactionmixture was extracted with EtOAc (20 mL×2), washed with brine and thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified via PrepHPLC (Petroleum ether/EtOAc) to give the title compound (30 mg, 43.3%yield) as a white solid. LC-MS: Calculated exact mass=222.1; Found[M+H]⁺=223.0. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.57 (d, J=4.3 Hz, 1H),8.05 (s, 1H), 7.79 (td, J=8.0, 1.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.31(dd, J=6.5, 5.4 Hz, 1H), 5.00 (dd, J=9.0, 4.9 Hz, 1H), 2.94-2.73 (m,2H), 2.56-2.44 (m, 1H), 2.39-2.23 (m, 1H).

Example 7. Synthesis of 1-phenylpyrimidine-2,4(1H,3H)-dione (I-27)

Step A: 1-phenylpyrimidine-2,4(1H,3H)-dione (I-27). To a mixture ofpyrimidine-2,4(1H,3H)-dione (224 mg, 2.0 mmol), iodobenzene (490 mg, 2.4mmol) and N-(2-cyanophenyl)picolinamide (89 mg, 0.4 mmol) in DMSO (8 mL)was added CuI (40 mg, 0.2 mmol) and K₃PO₄ (890 mg, 4.2 mmol) and themixture was stirred at 80° C. for 16 h. To the mixture was added H₂O (50mL) and it was extracted with EtOAc (50 mL×2). The combined organiclayer was washed with brine (50 mL×3), dried over Na₂SO₄, filtered,concentrated in vacuo, and purified via prep-TLC (Petroleum ether/EtOAc)to give the title compound (112 mg, 30% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d6) δ ppm: 11.43 (s, 1H), 7.72-7.70 (d, 1H), 7.51-7.48(m, 2H), 7.44-7.40 (m, 3H), 5.68-5.65 (dd, J1=2.0 Hz, J2=2.0 Hz, 1H).LC-MS: Calculated exact mass=188.1; Found [M+H]⁺=189.0.

Example 8. Synthesis of 1-phenyldihydropyrimidine-2,4(1H,3H)-dione(I-20)

Step A: 1-phenyldihydropyrimidine-2,4(1H,3H)-dione (I-20). A mixture of1-phenylpyrimidine-2,4(1H,3H)-dione (60 mg, 0.3 mmol) in MeOH (5 mL) wasadded Pd/C (10 mg) under N₂. The reaction mixture was degassed andpurged with H₂ several times. The mixture was stirred at r.t. under H₂balloon for 16 h. The reaction was filtered and the filtrate wasconcentrated in vacuo to give the title compound (46.6 mg, 78% yield) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 15.11 (s. 1H), 7.41-7.37(m, 2H), 7.34-7.31 (m, 2H), 7.25-7.21 (m, 1H), 3.80-3.77 (t, J=6.6 Hz,2H), 2.72-2.68 (t, J=6.6 Hz, 2H). LC-MS: Calculated exact mass=190.1;Found [M+H]⁺=191.0.

Example 9. Synthesis of 1-(pyridin-2-yl)pyrimidine-2,4(1H,3H)-dione and1-(pyridin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (I-28 and I-21)

Step A: 1-(pyridin-2-yl)pyrimidine-2,4(1H,3H)-dione (I-28). To a mixtureof pyrimidine-2,4(1H,3H)-dione (300 mg, 2.68 mmol), 2-bromopyridine (352mg, 2.23 mmol), K₃PO₄ (1.2 g, 5.63 mmol), and(1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (380 mg, 2.68 mmol) inDMSO (5 mL) was added copper(I) iodide (51 mg, 0.268 mmol). The mixturewas sealed, purged with nitrogen, and then heated at 60° C. for 24 h.The mixture was poured into water (20 mL), extracted with EtOAc (20mL×5), and the combined organic layers were concentrated under reducedpressure. The residue was purified by prep-TLC eluting withEtOAc/DCM=1/1 to give the title compound (240 mg, 56.6% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm: 11.54 (br. s., 1H),8.49-8.60 (m, 1H), 8.05 (d, J=8.00 Hz, 1H), 7.92-8.02 (m, 1H), 7.75 (d,J=8.26 Hz, 1H), 7.44-7.47 (m, 1H), 5.74-5.80 (m, 1H). LC-MS: Calculatedexact mass=189.1; Found [M+H]⁺=190.0.

Step B: 1-(pyridin-2-yl)dihydropyrimidine-2,4(1H,3H)-dione (I-21). To asolution of 1-(pyridin-2-yl)pyrimidine-2,4(1H,3H)-dione (42 mg, 0.222mmol) in MeOH (2 mL) was added Pd/C catalyst (20 mg, 10 percent bymass). Then the reactor was placed under H₂, purged three times at 5 barof H₂, then placed under 1 atm and stirred for 18 h. The mixture wasfiltered, the filture was concentrated under reduced pressure. Theresidue was purified by prep HPLC to give the title compound (10.2 mg,24.1% yield) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ ppm:8.34-8.47 (m, 1H), 7.88 (d, J=8.38 Hz, 1H), 7.72-7.78 (m, 1H), 7.70 (br.s., 1H), 7.07-7.18 (m, 1H), 4.26 (t, J=6.63 Hz, 2H), 2.82 (t, J=6.63 Hz,2H). LC-MS: Calculated exact mass=191.1; Found [M+H]⁺=192.0.

Example 10. Synthesis of 1-Benzyl-dihydro-pyrimidine-2,4-dione (I-24)

Step A: 1-Benzyl-dihydro-pyrimidine-2,4-dione (I-24). A solution of3-benzylamino-propionic acid ethyl ester (208 mg, 1.00 mmol) in HCl(aq., 6 M, 1.0 mL) was added dropwise into another solution of KNCO (100mg, 1.20 mmol, in 0.5 mL of water) at r.t. under nitrogen. The reactionmixture was stirred at 20° C. under N₂ for 12 hours. Then the reactionwas quenched by sat. NaHCO₃ aq. (10.0 mL) and extracted with EtOAc (20mL×3). The combined organic layer was washed with brine and dried overNa₂SO₄. The mixture was filtered and the filtrate solvent was removedunder reduced pressure. The residue was purified via silica gel columnchromatography (Petroleum ether/EtOAc) to give the title compound (14.4mg, 20.4% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.50(s, 1H), 7.39-7.28 (m, 5H), 4.62 (s, 2H), 3.34 (t, J₁=6.8 Hz, 2H), 2.62.(t, J₁=6.8 Hz, 2H). LC-MS: Calculated exact mass=204.1; Found[M+H]⁺=205.2.

Example 11. Synthesis of 1-Benzyl-dihydro-pyrimidine-2,4-dione (I-25)

Step A: 3-[(Pyridin-2-ylmethyl)-amino]-propionic acid ethyl ester (2).To a solution of C-pyridin-2-yl-methylamine (342 mg, 3.00 mmol) and TEA(202 mg, 2.00 mmol) in toluene (15.0 mL) was added 3-bromo-propionicacid ethyl ester (221 mg, 1.00 mmol) at r.t. under nitrogen. Thereaction mixture was stirred at 20° C. under N₂ for 12 hours. Thereaction mixture was quenched by water (30 mL) and extracted with EtOAc(50 mL×3). The combined organic layer was washed with brine 3 times anddried over Na₂SO₄. The mixture was filtered and the filtrate solvent wasremoved under reduced pressure to give the title compound (150 mg, 71.2%yield) as a white solid. LC-MS: Calculated exact mass=208.1; Found[M+H]⁺=209.1.

Step B: 1-Benzyl-dihydro-pyrimidine-2,4-dione (I-25). A solution of3-[(pyridin-2-ylmethyl)-amino]-propionic acid ethyl ester (208 mg, 1.00mmol) in HCl (aq., 6 M, 1.5 mL) was added dropwise into another solutionof KNCO (105.3 mg, 1.30 mmol, in 1.5 mL of water) at r.t. undernitrogen. The reaction mixture was stirred at 20° C. under N₂ for 12hours. Then the reaction mixture was quenched by sat. NaHCO₃ aq. (10.0mL) and extracted with EtOAc (20 mL×3). The combined organic layer waswashed with brine and dried over Na₂SO₄. The mixture was filtered andthe filtrate solvent was removed under reduced pressure. The residue waspurified via silica gel column chromatography (Petroleum ether/EtOAc) togive the title compound (15 mg, 7.31% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 8.57 (d J₁=2.8 Hz, 1H), 7.75-7.67 (m, 2H),7.34 (d, J₁=7.6 Hz, 1H), 7.24 (m, 1H), 4.74 (s, 2H), 3.55 (t, J₁=6.8 Hz,2H), 2.70. (t, J₁=6.8 Hz, 2H). LC-MS: Calculated exact mass=205.1; Found[M+H]⁺=206.1.

Example 12. Synthesis of 4-((2,6-dioxopiperidin-3-yl)thio)benzoic acid(I-10)

Step A: 4-((2,6-dioxopiperidin-3-yl)thio)benzoic acid (I-10). A mixtureof 4-mercaptobenzoic acid (200 mg, 1.30 mmol),3-bromopiperidine-2,6-dione (250 mg, 1.30 mmol), and Cs₂CO₃ (509 mg,1.56 mmol) in DMF (20 mL) was stirred for 1 h at rt. To the mixture wasadded H₂O (50 mL) and it was then extracted with EtOAc (50 mL×2). Thecombined organic layer was washed with brine (50 mL×3), dried overNa₂SO₄, filtered, concentrated in vacuo, and purified by columnchromatography (DCM/MeOH=10/1) to give4-((2,6-dioxopiperidin-3-yl)thio)benzoic acid (120 mg, 35% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm: 12.98 (s, 1H), 10.98 (s,1H), 7.88-7.85 (m, 2H), 7.55-7.53 (m, 2H), 4.58-4.55 (dd, J=4.4 Hz,J=8.8 Hz, 1H), 2.64-2.53 (m, 2H), 2.29-2.25 (m, 1H), 2.04-1.99 (m, 1).LC-MS: Calculated exact mass=265.29; Found [M+H]⁺=266.1.

Example 13. Synthesis of 4-((2,6-dioxopiperidin-3-yl)thio)benzamide(I-58)

Step A: 4-((2,6-dioxopiperidin-3-yl)thio)benzamide (I-58). To a mixtureof 4-((2,6-dioxopiperidin-3-yl)thio)benzoic acid (100 mg, 0.377 mmol)(I-10), HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (172 mg, 0452 mmol), and DIPEA(diisopropylethylamine) (584 mg, 4.53 mmol) in DMF (10 mL) was addedNH₄Cl (240 mg, 0.453 mmol) at rt. The mixture was stirred for 1 h at rt.To the mixture was added H₂O (50 mL), extracted with EtOAc (50 mL×2).The combined organic layer was washed with brine (50 mL×3), dried overNa₂SO₄, filtered, concentrated in vacuo and purified by columnchromatography (DCM/MeOH=10/1) to give4-((2,6-dioxopiperidin-3-yl)thio)benzamide (I-13) (20 mg, 20% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm: 10.96 (s, 1H), 7.97 (s,1H), 7.84-7.82 (d, J=8.0 Hz, 2H), 7.52-7.50 (d, J=8.0 Hz, 2H), 7.37 (s,1H), 4.52-4.49 (dd, J=4.4 Hz, J=8.0 Hz, 1H), 2.61-2.56 (m, 2H),2.27-2.23 (m, 1H), 2.01-1.96 (m, 1H). LC-MS: Calculated exactmass=264.06; Found [M+H]⁺=265.0.

Example 14. Synthesis ofN-[4-(2,6-Dioxo-piperidin-3-ylsulfanyl)-phenyl]-acetamide (I-13)

Step A: N-[4-(2,6-Dioxo-piperidin-3-ylsulfanyl)-phenyl]-acetamide(I-13). To a solution of N-(4-mercapto-phenyl)-acetamide (200 mg, 1.20mmol) in DMF (5.0 mL) was added Cs₂CO₃ (469 mg, 1.44 mmol) at r.t. undernitrogen. The reaction mixture was stirred at 20° C. under N₂ for 20minutes. Then 3-bromo-piperidine-2,6-dione (213 mg, 1.1 mmol) was addedslowly. After stirring at r.t. for 10 minutes, TLC (Petroleumether/EtOAc=1/1, silica gel plate) showed complete consumption of thestarting material. Then the reaction was quenched by water (30 mL) andextracted with EtOAc (50 mL×3). The combined organic layer was washedwith brine and dried over Na₂SO₄. The mixture was filtered and thefiltrate solvent was removed under reduced pressure. The residue waspurified via silica gel column chromatography (Petroleum ether/EtOAc) togive the title compound (56.7 mg, 20.3% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 10.87 (s, 1H), 10.05 (s, 1H), 7.57 (d, J=8.8Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 4.13. (m, 1H), 2.53 (m, 2H), 2.18 (m,1H), 2.04 (s, 3H), 1.88 (m, 1H). LC-MS: Calculated exact mass=278.1;Found [M+H]⁺=279.1.

Example 15. Synthesis of 3-(4-Amino-phenylsulfanyl)-piperidine-2,6-dione(I-14)

Step A: 3-(4-Amino-phenylsulfanyl)-piperidine-2,6-dione (I-14). To asolution of 4-amino-benzenethiol (125 mg, 1.00 mmol) in DMF (3.0 mL) wasadded Cs₂CO₃ (390 mg, 1.20 mmol) at r.t. under nitrogen. The reactionmixture was stirred at 20° C. under N₂ for 20 minutes. Then3-bromo-piperidine-2,6-dione (220 mg, 1.10 mmol) was added slowly. Afterstirring at r.t. for 10 minutes, TLC (Petroleum ether/EtOAc=1/1, silicagel plate) showed complete consumption of the starting material. Thenthe reaction was quenched by water (30 mL) and extracted with EtOAc (50mL×3). The combined organic layer was washed with brine and dried overNa₂SO₄. The mixture was filtered and the filtrate solvent was removedunder reduced pressure. The residue was purified via silica gel columnchromatography (Petroleum ether/EtOAc) to give the title compound (11.0mg, 4.6% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.77(s, 1H), 7.17 (dd, J₁=11.2 Hz, J₂=2.8 Hz, 2H), 6.52 (dd, J₁=11.2 Hz,J₂=2.8 Hz, 2H), 5.42. (m, 2H), 3.82 (m, 1H), 2.45 (m, 2H), 2.14 (m, 1H),1.81 (m, 1H). LC-MS: Calculated exact mass=236.1 Found [M+H]⁺=237.1.

Example 16. Synthesis of 3-((4-methoxyphenyl)thio)piperidine-2,6-dione(I-9)

Step A: 3-((4-methoxyphenyl)thio)piperidine-2,6-dione (I-9). A mixtureof 4-methoxybenzenethiol (300 mg, 2.14 mmol),3-bromopiperidine-2,6-dione (494 mg, 2.57 mmol), and Cs₂CO₃ (1.05 mg,3.22 mmol) in DMF (20 mL) was stirred for 1 h at rt. To the mixture wasadded H₂O (50 mL) and it was extracted with EtOAc (50 mL×2). Thecombined organic layer was washed with brine (50 mL×3), dried overNa₂SO₄, filtered, concentrated in vacuo, and purified by columnchromatography (Petroleum ether/EtOAc=1/1) to give the title compound(130 mg, 24% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) ppm: δ7.67 (s, 1H), 7.48 (d, J=8.9 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 3.86-3.78(m, 4H), 2.87 (ddd, J=17.8, 11.0, 5.4 Hz, 1H), 2.59 (dt, J=17.9, 4.9 Hz,1H), 2.34-2.21 (m, 1H), 2.18-2.10 (m, 1H). LC-MS: Calculated exactmass=251.1; Found [M+H]⁺=252.0.

Example 17. Synthesis of 3-((4-ethylphenyl)thio)piperidine-2,6-dione(I-17)

Step A: 3-((4-ethylphenyl)thio)piperidine-2,6-dione (I-17). To asolution of 3-bromopiperidine-2,6-dione (519.0 mg, 2.72 mmol) in DMF (30mL) was added 4-ethylbenzenethiol (250 mg, 1.812 mmol), Cs₂CO₃ (886.1mg, 2.72 mmol) at r.t. The reaction mixture was stirred at r.t. for 0.5hours. TLC (Petroleum ether/EtOAc=5/1; silica gel plate) showed completeconsumption of the starting material after this time. The reactionmixture was extracted with EtOAc (50 mL×2), washed with brine, and thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified via columnchromatography (Petroleum ether/EtOAc) to give the title compound (201.1mg, 44.6% yield) as a white solid. LC-MS: Calculated exact mass=249.1;Found [M+H]⁺=250.1. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.88 (s, 1H), 7.46(d, J=8.0 Hz, 2H), 7.19 (d, J=7.9 Hz, 2H), 3.91 (t, J=4.2 Hz, 1H),2.96-2.79 (m, 1H), 2.74-2.54 (m, 3H), 2.39-2.24 (m, 1H), 2.15 (dt,J=14.2, 4.9 Hz, 1H), 1.23 (t, J=7.6 Hz, 3H).

Example 18. Synthesis of 3-((4-chlorophenyl)thio)piperidine-2,6-dione(I-15)

Step A: 3-((4-chlorophenyl)thio)piperidine-2,6-dione (I-15). A mixtureof 3-bromopiperidine-2,6-dione (191 mg, 1 mmol), 4-chlorobenzenethiol(145 mg, 1 mol), and Cs₂CO₃ (654 mg, 2 mmol) in DMF (5 mL) was stirredat room temperature for 2 h. The mixture was poured into water (20 mL),extracted with EtOAc (20 mL×3), the combined organic layers were washedwith water (30 mL×2), and concentrated under reduced pressure. Theresidue was purified by Prep-TLC plate eluting with Petroleumether/EtOAc=1/1 to give the title compound (102 mg, 40% yield) as awhite solid. LC-MS: Calculated exact mass=255.0; Found [M+H]⁺=256.0. ¹HNMR (400 MHz, DMSO-d6) δ ppm: 10.93 (s, 1H), 7.47-7.54 (m, 2H),7.39-7.46 (m, 2H), 4.35 (dd, J=8.38, 4.75 Hz, 1H), 2.53-2.59 (m, 2H),2.16-2.26 (m, 1H), 1.96 (dd, J=13.57, 7.32 Hz, 1H).

Example 19. Synthesis of3-((4-(trifluoromethyl)phenyl)thio)piperidine-2,6-dione (I-16)

Step A: 3-((4-(trifluoromethyl)phenyl)thio)piperidine-2,6-dione (I-16).A mixture of 4-(trifluoromethyl)benzenethiol (300 mg, 1.69 mmol),3-bromopiperidine-2,6-dione (388 mg, 2.02 mmol), and Cs₂CO₃ (826 mg,2.54 mmol) in DMF (20 mL) was stirred for 1 h at rt. To the mixture wasadded H₂O (50 mL), extracted with EtOAc (50 mL×2). The combined organiclayer was washed with brine (50 mL×3), dried over Na₂SO₄, filtered,concentrated in vacuo and purified by column chromatography (Petroleumether/EtOAc=1/1) to give the title compound (180 mg, 37% yield) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: (s, 1H), 7.65-7.58 (dd,J=8.0 Hz, J=20.8 Hz, 4H), 4.15-4.10 (dd, J=7.6 Hz, J=14.4 Hz, 1H),2.90-2.81 (m, 1H), 2.70-2.63 (m, 1H), 2.44-2.36 (m, 1H), 2.25-2.19 (m,1H). LC-MS: Calculated exact mass=289.04; Found [M+H]⁺=290.0.

Example 20. Synthesis of3-(1-Methyl-1H-benzoimidazol-2-ylsulfanyl)-piperidine-2,6-dione (I-12)

Step A: 3-(1-Methyl-1H-benzoimidazol-2-ylsulfanyl)-piperidine-2,6-dione(I-12). To a solution of 1-methyl-1H-benzoimidazole-2-thiol (164 mg,1.00 mmol) in DMF (5.0 mL) was added Cs₂CO₃ (440 mg, 1.40 mmol) at r.t.under nitrogen. The reaction mixture was stirred at 20° C. under N₂ for20 minutes. Then 3-bromo-piperidine-2,6-dione (195 mg, 1.00 mmol) wasadded slowly. After stirring at r.t. for 10 minutes, TLC (Petroleumether/EtOAc=1/1, silica gel plate) showed complete consumption of thestarting material. Then the reaction was quenched by water (30 mL) andextracted with EtOAc (50 mL×3). The combined organic layer was washedwith brine and dried over Na₂SO₄. The mixture was filtered and thefiltrate solvent was removed under reduced pressure. The residue waspurified via silica gel column chromatography (Petroleum ether/EtOAc) togive title compound (94.7 mg, 28.9% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm: 11.05 (s, 1H), 7.56-7.50 (m, 2H),7.22-1.15 (m, 2H), 4.90 (m, 1H), 3.74 (s, 3H) 2.73 (m, 1H) 2.61 (m, 1H),2.40 (m, 1H), 2.33 (m, 1H). LC-MS: Calculated exact mass=275.1 Found[M+H]⁺=275.2.

Example 21. Synthesis of3-((1-ethyl-1H-benzo[d]imidazol-2-yl)thio)piperidine-2,6-dione (I-11)

Step A: 2-chloro-1-ethyl-1H-benzo[d]imidazole (2). To a solution of2-chloro-1H-benzo[d]imidazole (1 g, 6.553 mmol) in DMF (50 mL) was addedNaH (340.8 mg, 8.519 mmol) at 0° C. After 15 minutes, bromoethane (1.33g, 8.519 mmol) was added to the reaction mixture at 0° C. The reactionmixture was stirred at r.t. for 2 hours. TLC (Petroleum ether/EtOAc=5/1;silica gel plate) showed complete consumption of the starting materialafter this time. The mixture was quenched by water at 0° C. The reactionmixture was extracted with EtOAc (50 mL×2), washed with brine and thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified via columnchromatography (Petroleum ether/EtOAc) to give the title compound (1.1g, 92.7% yield) as a white solid. LC-MS: Calculated exact mass=180.1;Found [M+H]⁺=181.1.

Step B: 1-ethyl-1H-benzo[d]imidazole-2-thiol (3). A solution of2-chloro-1-ethyl-1H-benzo[d]imidazole (1.1 g, 6.111 mmol) in EtOH (50mL) was treated with thiourea (697.6 mg, 9.167 mmol) at r.t. Thereaction mixture was heated at reflux for 12 hours. TLC (Petroleumether/EtOAc=10/1; silica gel plate) showed complete consumption of thestarting material after this time. The reaction mixture solvent wasremoved under reduced pressure and the mixture was purified via columnchromatography (Petroleum ether/EtOAc) to give the title compound (778.1mg, 71.5% yield) as a white solid. LC-MS: Calculated exact mass=178.1;Found [M+H]⁺=179.1.

Step C: 3-((1-ethyl-1H-benzo[d]imidazol-2-yl)thio)piperidine-2,6-dione(I-11). To a solution of 3-bromopiperidine-2,6-dione (139.5 mg, 0.730mmol) in DMF (15 mL) was added 1-ethyl-1H-benzo[d]imidazole-2-thiol (100mg, 0.562 mmol), and Cs₂CO₃ (238 mg, 0.730 mmol) at r.t. The reactionmixture was stirred at r.t. for 0.5 hours. TLC (Petroleumether/EtOAc=5/1; silica gel plate) showed complete consumption of thestarting material after this time. The reaction mixture was extractedwith EtOAc (50 mL×2), washed with brine and the combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified via column chromatography (Petroleumether/EtOAc) to give the title compound (93.1 mg, 57.3% yield) as awhite solid. LC-MS: Calculated exact mass=289.1; Found [M+H]⁺=290.1. ¹HNMR (400 MHz, CDCl₃) δ ppm: 8.05 (s, 1H), 7.73-7.65 (m, 1H), 7.35-7.26(m, 3H), 5.11 (s, 1H), 4.24 (q, J=7.7 Hz, 2H), 2.93-2.77 (m, 2H),2.76-2.62 (m, 1H), 2.46-2.30 (m, 1H), 1.44 (t, J=7.3 Hz, 3H).

Example 22. Synthesis of3-(1-Isopropyl-1H-benzoimidazol-2-ylsulfanyl)-piperidine-2,6-dione(I-60)

Step A: 2-Chloro-1-isopropyl-1H-benzoimidazole (2). To a solution of2-Chloro-1-isopropyl-1H-benzoimidazole (167.5 mg, 1.00 mmol) in DMF (4mL) was added NaH (60% in mineral oil, 36 mg, 1.2 mmol) at 0° C. Afterstirring 30 minutes at r.t., 2-Bromo-propane (244 mg, 1.20 mmol) wasadded dropwise and the reaction mixture was stirred at 37° C. for 12hours. Then the reaction was quenched by water (30 mL) and extractedwith EtOAc (50 mL×3). The combined organic layer was washed with brineand dried over Na₂SO₄. The mixture was filtered and the filtrate solventwas removed under reduced pressure. The residue was purified via silicagel column chromatography (Petroleum ether/EtOAc) to give the titlecompound (105 mg, 53.2% yield) as a white solid. LC-MS: Calculated exactmass=194.1; Found [M+H]⁺=195.2; 197.2.

Step B: 1-Isopropyl-1H-benzoimidazole-2-thiol (3). To a solution of2-Chloro-1-isopropyl-1H-benzoimidazole (1.3 g, 0.57 mmol) in EtOH (50mL) was added thiourea (800 mg). The reaction mixture was stirred at 90°C. for 3 hours. The reaction mixture solvent was removed under reducedpressure and the residue was purified via column chromatography directly(Petroleum ether/EtOAc) to give title compound (1.02 g, 91.4% yield) asa yellow solid. LC-MS: Calculated exact mass=192.1; Found [M+H]⁺=193.3.

Step C:3-(1-Isopropyl-1H-benzoimidazol-2-ylsulfanyl)-piperidine-2,6-dione(I-60). To a solution of 1-Isopropyl-1H-benzoimidazole-2-thiol (192 mg,1.00 mmol) in DMF (5.0 mL) was added Cs₂CO₃ (440 mg, 1.40 mmol) at r.t.under nitrogen. The reaction mixture was stirred at 20° C. under N₂ for20 minutes. Then 3-Bromo-piperidine-2,6-dione (232.8 mg, 1.40 mmol) wasadded slowly. After stirring at r.t. for 10 minutes, TLC (Petroleumether/EtOAc=1/1, silica gel plate) showed complete consumption of thestarting material. Then the reaction was quenched by water (30 mL) andextracted with EtOAc (50 mL×3). The combined organic layer was washedwith brine and dried over Na₂SO₄. The mixture was filtered and thefiltrate solvent was removed under reduced pressure. The residue waspurified via silica gel column chromatography (Petroleum ether/EtOAc) togive the title compound (94.7 mg, 31.2% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d6) δ ppm: 11.03 (s, 1H), 7.67 (m, 1H), 7.56 (m, 1H),7.16 (m, 2H), 4.92 (m, 1H) 4.80 (m, 1H) 2.78-2.70 (m, 1H), 2.60 (m, 1H),2.45 (m, 1H), 2.30 (m, 1H), 1.57 (d, J=6.8 Hz 6H). LC-MS: Calculatedexact mass=303.1; Found [M+H]⁺=304.1.

Example 23. Synthesis of3-(imidazo[1,5-a]pyridin-3-ylthio)piperidine-2,6-dione (I-61)

Step A: imidazo[1,5-a]pyridine-3-thiol (2). To a solution ofpyridin-2-ylmethanamine (159 mg, 1.48 mmol) in xylenes (5 mL) was addedisothiocyanatobenzene (200 mg, 1.48 mmol) slowly with cooling on ice.The resulting solution was heated at 145° C. and refluxed for 3 h, andthen allowed to cool to rt and stirred for 12 h. To the mixture wasadded H₂O (50 mL) and it was extracted with EtOAc (50 mL×2). Thecombined organic layer was washed with brine (50 mL×3), dried overNa₂SO₄, filtered, concentrated in vacuo and purified via columnchromatography (Petroleum ether/EtOAc=2/1) to give the title compound(180 mg, 81% yield) as a green solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: δ12.16 (s, 1H), 8.25 (d, J=7.4 Hz, 1H), 7.20 (d, J=9.4 Hz, 1H), 7.04 (s,1H), 6.76 (dd, J=9.2, 6.4 Hz, 1H), 6.58 (t, J=6.9 Hz, 1H). LC-MS:Calculated exact mass=150.0; Found [M+H]⁺=151.1.

Step B: 3-(imidazo[1,5-a]pyridin-3-ylthio)piperidine-2,6-dione (I-61). Amixture of imidazo[1,5-a]pyridine-3-thiol (180 mg, 1.20 mmol),3-bromopiperidine-2,6-dione (275 mg, 1.44 mmol), Cs₂CO₃ (587 mg, 1.80mmol) in DMF (10 mL) was stirred for 1 h at rt. To the mixture was addedH₂O (50 mL) and it was extracted with EtOAc (50 mL×2). The combinedorganic layer was washed with brine (50 mL×3), dried over Na₂SO₄,filtered, concentrated in vacuo, and purified via column chromatography(DCM/EtOAc=1/1) to give the title compound (30 mg, 10% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) ppm: δ 8.42 (dd, J=7.1, 0.8 Hz, 1H), 7.82(s, 1H), 7.62 (s, 1H), 7.55-7.47 (m, 1H), 6.94 (dd, J=9.0, 6.5 Hz, 1H),6.81 (t, J=6.8 Hz, 1H), 4.22-4.12 (m, 1H), 2.98 (ddd, J=17.9, 8.5, 5.1Hz, 1H), 2.66 (ddd, J=17.9, 7.4, 5.1 Hz, 1H), 2.41 (ddd, J=13.6, 9.8,5.0 Hz, 1H), 2.25 (dtd, J=12.2, 7.2, 5.0 Hz, 1H). LC-MS: Calculatedexact mass=261.1 Found [M+H]⁺=262.0.

Example 24. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) Assay

Equal volumes of His-tagged CRBN-DDB1 complex (56 nM) was mixed withEu-cryptate labeled Anti-6HIS-monoclonal antibody (50× dilution from thecommercial stock solution, Vender: Cisbio, Cat. #61HI2KLA) in a finalbuffer containing 20 mM HEPES pH 7.0, 150 mM NaCl, 0.005% Tween-20. Thesolution was then mixed with Cy5-labeled thalidomide (final 8 nM) andvarious concentrations of compounds (a serial 3-fold dilution with thetop concentration 200 μM). The mixture were incubated at roomtemperature for 1 hour. FRET signals were measured on an EnVision platereader (Perkin Elmer) by exciting at 340 nm and recording emission atboth 615 nm as no FRET control and 665 nm as the FRET signals with a 60microsecond delay. FRET efficiency was calculated as the ratio offluorescent signals at 665 nM/615 nM. Quantitative loss of FRETefficiency as a function of compound concentrations was fitted by afour-parameter Logistic Function using GraphPad Prism 7.0 and the IC50values were reported for each compound.

Table 3 shows the results for selected compounds in the time-resolvedfluorescence resonance energy transfer (TR-FRET) assay. The compoundnumbers correspond to the compound numbers in Table 1. Compounds havingan activity designated as “A” provided an IC₅₀ of <1 μM; compoundshaving an activity designated as “B” provided an IC₅₀ of 1-10 μM;compounds having an activity designated as “C” provided an IC₅₀ of10-100 μM; and compounds having an activity designated as “D” providedan IC₅₀ of >100 μM. For reference, the known CRBN binders provided thefollowing IC₅₀ values in the TR-FRET assay: KT-377 (IC₅₀=0.63 μM) andpomalidomide (IC₅₀=1.75 μM).

TABLE 3 TR-FRET Assay Results Compound # CRBN HTRF IC₅₀ (μM) I-4 C I-6 CI-7 C I-8 B I-9 C I-10 C I-11 B I-12 C I-13 C I-14 C I-15 C I-16 C I-17B I-20 C I-21 D I-24 C I-25 C I-27 C I-28 D I-38 C I-39 D I-62 C I-63 CI-64 C I-65 C I-66 C I-67 C I-68 B I-69 C I-70 C I-71 D I-72 C I-73 DI-74 B I-75 C I-76 D I-77 D I-78 B I-79 B I-80 C I-81 D I-82 D I-83 CI-84 B I-85 B I-86 B I-87 B I-88 C I-89 C I-90 B I-92 C I-93 C I-94 BI-95 C I-96 C I-97 B I-98 C I-99 B I-101 B I-102 C I-103 C I-104 B I-106C I-107 C I-108 B I-109 C I-110 B I-111 B I-112 C I-113 C I-114 C I-115B I-116 D I-117 C I-118 C I-119 B I-120 C I-121 B I-122 B I-123 C I-124B I-125 B I-126 B I-127 C I-128 C I-129 C I-130 B I-131 C I-132 C I-133C I-134 C I-135 B I-136 B I-137 C I-138 B I-139 B I-140 B I-141 C I-142B I-143 D I-144 D I-145 D I-146 D

Example 25. Fluorescence Polarization (FP) Assay

Untagged CRBN-DDB1 complex (final 50 nM) was mixed with Cy5-labeledthalidomide (final 20 nM) and various concentrations of compounds (aserial 3-fold dilution with the top concentration of 200 μM). The finalsolution contained 50 mM HEPES, 200 mM NaCl and 2 mM DTT, pH 7.5. Themixtures were incubated at room temperature for 10 min. The FP signalswere recorded on an EnVision plate reader (Perkin Elmer) using thefollowing settings: Excitation Light (%): 100; Measurement Height: 12;G-Factor: 1; Detector Gain 1: 500; Detector Gain 2: 500; Flash Number:100. Dose-dependent loss of FP signals was fitted by four-parameterLogistic Function using GraphPad Prism 7.0 and the IC50 values werereported for each compound.

Results for selected compounds will be determined in the fluorescencepolarization (FP) assay. For reference, the known CRBN binders providedthe following IC₅₀ values in the FP assay: thalidomide (IC₅₀=2.4 μM) andpomalidomide (IC₅₀=1.15 μM).

Example 26. Synthesis of 3-(4-ethylphenoxy)piperidine-2,6-dione (I-78)

3-Bromopiperidine-2,6-dione (26.2)

To a stirred solution of piperidine-2,6-dione (30 g, 0.266 mol) in CHCl₃(60 mL) was added Br₂ (13.5 mL, 0.265 mol) in a sealed tube, then thereaction mixture was heated to 113° C. for 1.5 h. The color of thereaction mixture changed from deep yellow to pale yellow. The mixturewas cooled to r.t. and transferred to a round bottom flask, concentratedto dry. To the residue was added 100 mL ice water, basified to pH=8 withsaturated NaHCO₃, extracted with DCM (100 mL×5). The organic layers weredried with Na₂SO₄, filtered, concentrated to dry to give crude product,which was dissolved in a solution of DCM:EtOAc=1:1 (˜90 mL), then heatedto 80° C., after the solid was completely dissolved, stopped the heatingtreatment, cooled to r.t. for overnight. The solution was filtered; thesolid was collected, dried under vacuum to give the desired product3-bromopiperidine-2,6-dione (15.7 g) as a white solid. The filtrate wasconcentrated to give the crude product, and the crude product waspurified by column chromatography on silica gel eluting withDCM:Petroleum ether:EtOAc=5:5:1 to DCM:Petroleum ether:EtOAc=5:5:2 toobtain the second batch of desired product (12 g) as a white solid(total yield: 54.5%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H),5.00-4.78 (m, 1H), 2.69-2.54 (m, 2H), 2.45 (dd, J=10.0, 5.1 Hz, 1H),2.17-2.12 (m, 1H).

3-(4-Ethylphenoxy)piperidine-2,6-dione (I-78)

To a solution of 3-bromopiperidine-2,6-dione (200 mg, 1.045 mmol) inCH₃CN (10 mL) was added 4-ethylphenol (166.3 mg, 1.361 mmol), Cs₂CO₃(443.7 mg, 1.361 mmol) at r.t. The reaction mixture was heated at 40° C.for 3 h. TLC (50% Petroleum ether/50% EtOAc, silica gel plate) showed3-bromopiperidine-2,6-dione was consumed. The mixture was cooled tor.t., and filtered. The filtrate was concentrated in vacuo. The residuewas purified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%)to give the desired compound 3-(4-ethylphenoxy)piperidine-2,6-dione(49.1 mg, 20.2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s,1H), 7.13 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 4.83 (dd, J=7.6,4.3 Hz, 1H), 2.94 (ddd, J=17.9, 7.7, 5.3 Hz, 1H), 2.71-2.63 (m, 1H),2.63-2.57 (i, 2H), 2.40-2.20 (i, 2H), 1.21 (t, J=7.6 Hz, 3H); LC/MS(ESI, m/z): [M+1]⁺=234.1.

Characterization data for further compounds prepared by the above methodare presented in Table 4 below. Compounds in Table 4 were prepared bymethods substantially similar to those described to prepare I-78, where4-ethylphenol was replaced with the reagent as indicated in Table 4.

TABLE 4 Cpnd # Reagent Compound Characterization I-103

¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.36-7.29 (m, 2H), 7.04 (dd, J =7.8, 6.4 Hz, 3H), 4.88 (dd, J = 7.6, 4.4 Hz, 1H), 2.96 (ddd, J = 18.0,7.6, 5.4 Hz, 1H), 2.68 (ddd, J = 18.0, 7.7, 5.6 Hz, 1H), 2.43-2.23 (m,2H); LC/MS (ESI, m/z): [M + 1]⁺ = 206.1. I-125

¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 6.91- 6.87 (m, 2H), 6.70-6.66(m, 2H), 4.95-4.91 (m, 1H), 2.80 (s, 6H), 2.71-2.55 (m, 2H), 2.19-2.01(m, 2H); LC/MS (ESI, m/z): [M + 1]⁺ = 249.1. I-124

¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 7.09 (d, J = 8.6 Hz, 2H),6.92 (t, J = 5.8 Hz, 2H), 5.13 (dd, J = 10.7, 5.1 Hz, 1H), 2.76-2.65 (m,1H), 2.65-2.56 (m, 1H), 2.56- 2.51 (m, 2H), 2.24-2.05 (m, 2H), 1.58-1.46(m, 2H), 1.35-1.21 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); LC/MS (ESI, m/z):[M + 1]⁺ = 262.1. I-115

¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 7.33- 7.24 (m, 2H), 6.97-6.88(m, 2H), 5.14 (dd, J = 10.6, 5.2 Hz, 1H), 2.77-2.64 (m, 1H), 2.64-2.56(m, 1H), 2.25- 2.03 (m, 2H), 1.25 (d, J = 8.1 Hz, 9H); LC/MS (ESI, m/z):[M + 1]⁺ = 262.2. I-128

¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 6.93- 6.82 (m, 4H), 5.01 (dd,J = 10.4, 5.0 Hz, 1H), 3.05-2.99 (m, 4H), 2.74-2.52 (m, 4H), 2.47-2.41(m, 4H), 2.20 (s, 3H); LC/MS (ESI, mz): [M + 1]⁺ = 304.1. I-119

¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 7.86-7.83 (d, J = 8.8 Hz,2H), 7.76 (d, J = 8.0 Hz, 1H), 7.48-7.44 (m, 2H), 7.38-7.34 (m, 1H),7.26-7.23 (m, 1H), 5.41- 5.37 (m, 1H), 2.82-2.73 (m, 1H), 2.68-2.61 (m,1H), 2.32-2.18 (m, 2H); LC/MS (ESI, m/z): [M + 1]⁺ = 256.1. I-129

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.01 (d, J = 4.2 Hz, 1H),8.69 (s, 1H), 7.83-7.72 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.56 (d, J =7.3 Hz, 1H), 5.62-5.55 (m, 1H), 2.77-2.70 (m, 2H), 2.39-2.33 (m, 2H);LC/MS (ESI, m/z): [M + 1]⁺ = 257.1.

Example 27. Synthesis of3-((4-hydroxy-6-methylpyrimidin-2-yl)thio)piperidine-2,6-dione (I-95)

To a solution of 2-mercapto-6-methylpyrimidin-4-ol (200 mg, 1.41 mmol)in THE (5 mL) were added 3-bromopiperidine-2,6-di one (324 mg, 1.69mmol), Cs₂CO₃ (691 mg, 2.12 mmol). The reaction solution was stirred for3 h at rt. The reaction mixture was diluted with H₂O (50 mL), extractedwith EA (50 mL×2). The combined organic layers were washed with brine(50 mL×3), dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo.The residue was purified by column to give desired compound (7.2 mg, 2%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (s, 1H),10.97 (s, 1H), 5.97 (s, 1H), 4.68 (s, 1H), 2.71-2.61 (m, 1H), 2.56-2.51(m, 1H), 2.33-2.25 (m, 2H), 2.15 (s, 3H); LC/MS (ESI, m/z):[M+1]⁺=254.0.

Characterization data for further compounds prepared by the above methodare presented in Table 5 below. Compounds in Table 5 were prepared bymethods substantially similar to those described to prepare I-95, where27.1 was replaced with the reagent as indicated in Table 5.

TABLE 5 Cpnd # Reagent Compound Characterization I-100

¹H NMR (400 MHz, CDCl₃) δ 7.64 (s, 1H), 7.26-7.12 (m, 3H), 3.73 (t, J =4.1 Hz, 1H), 3.02-2.94 (m, 1H), 2.70- 2.53 (m, 1H), 2.53 (s, 6H),2.31-2.25 (m, 1H), 2.22- 2.13 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ =250.1. I-68

¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H),7.24 (d, J = 8.4 Hz, 2H), 4.22 (dd, J = 7.6, 4.8 Hz, 1H), 2.89-2.67 (m,1H), 2.57-2.51 (m, 1H), 2.22- 2.15 (m, 1H), 2.10-1.85 (m, 2H), 1.19 (d,J = 7.2 Hz, 6H); LC/MS (ESI, m/z): [M + 1]⁺ = 264.1. I-99

¹H NMR (400 MHz, CDCl₃) δ 7.75-7.63 (m, 2H), 7.45- 7.39 (m, 1H),7.35-7.27 (m, 2H), 4.05 (t, J = 4.7 Hz, 1H), 2.95-2.75 (m, 1H),2.70-2.62 (m, 1H), 2.2.42-2.30 (m, 1H), 2.25-2.12 (m, 1H); LC/MS (ESI,m/z): [M + 1]⁺ = 306.0. I-114

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.44-7.38 (m, 1H), 7.33-7.27 (m,1H), 7.20-7.10 (m, 1H), 3.89 (t, J = 5.0 Hz, 1H), 2.88-2.72 (m, 1H),2.70-2.61 (m, 1H), 2.43- 2.31 (m, 1H), 2.22-2.12 (m, 1H); LC/MS (ESI,m/z): [M + 1]⁺ = 258.0. I-123

¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H), 10.93 (s, 1H), 8.0 (t, J =4.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H),7.51-7.42 (m, 1H), 4.39 ((dd, J = 8.0, 4.0 Hz, 1H), 2.52-2.45 (m, 2H),2.33-2.15 (m, 1H), 1.93-1.75 (m, 1H); LC/MS (ESI, m/ z): [M + 1]⁺ =266.1. I-134

¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 7.96 (t, J = 1.5 Hz, 1H),7.82-7.71 (m, 2H), 7.55 (t, J = 7.9 Hz, 1H), 4.54 (dd, J = 9.0, 4.8 Hz,1H), 2.71-2.54 (m, 2H), 2.30-2.19 (m, 1H), 2.05-1.93 (m, 1H); LC/MS(ESI, m/z): [M + 1]⁺ = 247.1. I-122

¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H), 7.57 (d, J = 1.8 Hz, 1H),7.47-7.32 (m, 3H), 4.46 (dd, J = 8.7, 4.8 Hz, 1H), 2.68-2.53 (m, 2H),2.29-2.17 (m, 1H), 2.01- 1.95 (m, 1H); LC/MS (ESI, mz): [M + 1]⁺ =256.0. I-135

¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 7.35 (m, 2H), 6.85 (m, 2H),5.20-3.55 (m, 5H), 2.81-2.56 (m, 1H), 2.30-2.11 (m, 1H), 1.95-1.77 (m,1H), 1.24 (s, 1H), 1.06 (t, J = 6.2 Hz, 6H); LC/MS (ESI, m/z): [M + 1]⁺= 293.1. I-69

¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 7.31-7.22 (m, 3H), 7.12-7.10(d, J = 6, 8 Hz, 1H), 4.30-4.27 (m, 1H), 2.55 (t, J = 6.6 Hz, 2H), 2.29(s, 3H), 2.24-2.16 (m, 1H), 1.98-1.88 (m, 1H); LC/MS (ESI, m/z): [M +1]⁺ = 236.1. I-92

¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.15 (s, 2H), 7.97 (s, 1H),4.75 (dd, J = 9.2, 4.8 Hz, 1H), 2.65-2.50 (m, 2H), 2.31-2.26 (m, 1H),2.08-2.05 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 358.0 I-74

¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 9.97 (s, 1H), 7.36-7.34 (dd,J = 7.6, 1.6 Hz, 1H), 7.19-7.15 (m, 1H), 6.89-6.87 (dd, J = 8.4, 1.2 Hz,1H), 6.80-6.76 (m, 1H), 4.27 (dd, J = 7.2, 4.8 Hz, 1H), 2.62-2.45 (m,2H), 2.18-2.12 (m, 1H), 1.86-1.81 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ =238.0. I-75

¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 7.43 (dd, J = 7.6, 1.2 Hz,1H), 7.33-7.29 (m, 1H), 7.05-7.01 (m, 1H), 6.95-6.91 (m, 1H), 4.29 (dd,J = 7.6, 4.8 Hz, 1H), 3.83 (s, 3H), 2.57-2.48 (m, 2H), 2.17-2.15 (m,1H), 1.88-1.84 (m , 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 251.9. I-117

¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 7.88 (dd, J = 7.69, 1.06 Hz,1H), 7.74-7.81 (m, 1H), 7.70 (td, J = 7.75, 1.50 Hz, 1H), 7.48 (td, J =7.57, 1.13 Hz, 1H), 4.56 (dd, J = 9.13, 4.88 Hz, 1H), 2.52-2.69 (m, 2H),2.20- 2.28 (m, 1H), 1.97-2.12 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ =247.0. I-84

¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 7.40 (d, J = 8.2 Hz, 2H),7.19 (d, J = 8.2 Hz, 2H), 4.21 (dd, J = 7.8, 4.7 Hz, 1H), 2.63-2.51 (m,4H), 2.18 (m, 1H), 1.97-1.83 (m, 1H), 1.60-1.47 (m, 2H), 1.29 (m, 2H),0.89 (t, J = 7.3 Hz, 3H); LC/MS (ESI, m/z): [M + 1]⁺ = 278.1. I-85

¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 7.31 (d, J = 8.8 Hz, 2H),6.68 (d, J = 8.8 Hz, 2H), 3.89 (dd, J = 6.7, 4.7 Hz, 1H), 2.91 (s, 6H),2.61-2.52 (m, 1H), 2.44 (m, 1H), 2.12 (m, 1H), 1.87-1.76 (m, 1H); LC/MS(ESI, m/z): [M + 1]⁺ = 265.1. I-86

¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 7.25 (t, J = 7.9 Hz, 1H),7.07-6.95 (m, 2H), 6.85 (dd, J = 8.3, 1.7 Hz, 1H), 4.36 (dd, J = 8.2,4.7 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 2.56 (m, 2H), 2.30-2.14 (m, 1H),1.94 (m, 1H), 1.32 (t, J = 7.0 Hz, 3H); LC/MS (ESI, m/z): [M + 1]⁺ =266.0. I-87

¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H), 7.27 (t, J = 7.9 Hz, 1H),7.08-6.98 (m, 2H), 6.90-6.82 (m, 1H), 4.36 (dd, J = 8.1, 4.7 Hz, 1H),3.76 (s, 3H), 2.57-2.54 (m, 2H), 2.25- 2.16 (m, 1H), 1.99-1.88 (m, 1H);LC/MS (ESI, m/z): [M + 1]⁺ = 252.0. I-112

¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H),7.30 (d, J = 8.3 Hz, 2H), 5.23 (t, J = 5.7 Hz, 1H), 4.48 (d, J = 5.7 Hz,2H), 4.25 (dd, J = 7.9, 4.7 Hz, 1H), 2.56- 2.53 (m, 2H), 2.25-2.13 (m,1H), 1.92-1.90 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 234.0. I-66

¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H),7.18 (d, J = 8.0 Hz, 2H), 4.20 (m, 1H), 2.55-2.51 (m, 2H), 2.29 (s, 3H),2.19-2.15 (m, 1H), 1.95-1.90 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ =236.0. I-109

¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 7.7 Hz, 2H), 7.74 (d, J = 7.2 Hz,1H), 7.56 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 3.97 (t, J =4.6 Hz, 1H), 2.92-2.85 (m, 1H), 2.68- 2.62 (m, 1H), 2.42-2.31 (m, 1H),2.26-2.21 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 290.0. I-101

¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.39(d, J = 8.5 Hz, 1H), 7.28-7.25 (m, 1H), 4.14 (t, J = 4.9 Hz, 1H),2.93-2.85 (m, 1H), 2.70-2.65 (m, 1H), 2.46-2.32 (m, 1H), 2.27-2.15 (m,1H); LC/MS (ESI, m/z): [M + 1]⁺ = 291.9. I-102

¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.75 (s, 1H), 7.57 (s, 1H), 4.10(t, J = 4.9 Hz, 1H), 2.90-2.83 (m, 1H), 2.71-2.66 (m, 1H), 2.43-2.36 (m,1H), 2.27-2.17 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 325.9. I-179

¹H NMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.09(s, 1H), 6.99 (d, J = 7.8 Hz, 1H), 3.84 (t, J = 4.4 Hz, 1H), 2.95-2.88(m, 1H), 2.63-2.58 (m, 1H), 2.46 (s, 3H), 2.37-2.24 (m, 4H), 2.16-2.11(m, 1H); LC/MS (ESI, m/z: [M + 1]⁺ = 250.0. I-120

¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H),7.03 (d, J = 1.6 Hz, 1H), 6.77 (dd, J = 7.9, 1.6 Hz, 1H), 5.94 (s, 2H),4.09 (dd, J = 7.7, 4.8 Hz, 1H), 2.64- 2.53 (m, 2H), 2.17-2.11 (m, 1H),1.92-1.87 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 305.0. I-107

¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 7.38-7.25 (m, 5H), 3.91 (s,2H), 3.52 (t, J = 4.8 Hz, 1H), 2.52-2.47 (m, 2H), 2.29-2.28 (m, 1H),1.87-1.82 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 236.1. I-116

¹H NMR (400 MHz, CDCl₃) δ 7.82 (br. s., 1H), 3.68 (t, J = 3.75 Hz, 1H),2.89-3.06 (m, 1H), 2.76-2.83 (m, 1H), 2.58- 2.61 (m, 1H), 2.31-2.40 (m,1H), 2.03-2.22 (m, 2H), 1.86- 1.97 (m, 1H), 1.71-1.86 (m, 2H), 1.56-1.71(m, 1H), 1.17- 1.46 (m, 5H); LC/MS (ESI, m/z): [M + 1]⁺ = 228.1. I-98

¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 8.79 (d, J = 2.2 Hz, 1H),8.05 (dd, J = 8.6, 2.2 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 4.89 (dd, J =10.4, 5.6 Hz, 1H), 2.80-2.65 (m, 1H), 2.63- 2.53 (m, 1H), 2.36-2.18 (m,2H); LC/MS (ESI, m/z): [M + 1]⁺ = 291.0. I-136

¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.78(t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 4.61 (t, J = 12 Hz, 1H),2.83-2.71 (m, 2H), 2.52-2.45 (m, 2H); LC/MS (ESI, m/z): [M + 1]⁺ =267.0. I-126

¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 8.51-8.50 (m, 1H), 8.21-8.19(m, 1H), 7.23-7.20 (m, 1H), 4.80-4.76 (m, 1H), 2.73-2.64 (m, 1H),2.58-2.52 (m, 1H), 2.25-2.15 (m, 2H); LC/MS (ESI, m/z): [M + 1]⁺ =267.0. I-90

¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.49-8.48 (m, 1H), 7.83-7.80(m, 1H), 7.45-7.43 (d, J = 8.8 Hz, 1H), 4.80- 4.76 (dd, Ji = 5.2 Hz, J2= 4.8 Hz, 1H), 2.74-2.66 (m, 1H), 2.58-2.52 (m, 1H), 2.32-2.25 (m, 1H),2.22-2.13 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 257.0. I-62

¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.29-8.49 (m, 2H), 7.32-7.45(m, 2H), 4.71 (dd, J = 9.82, 4.82 Hz, 1H), 2.62- 2.76 (m, 1H), 2.52-2.61(m, 1H), 2.26-2.33 (m, 1H), 2.00-2.13 (m, 1H); LC/MS (ESI, m/z): : [M +1]⁺ = 223.1. I-110

¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.38-8.25 (d, J = 6.0 Hz,1H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.36 (m, 1H), 7.28-7.24 (m,1H), 4.60 (dd, J = 10.4, 4.9 Hz, 1H), 2.76- 2.57 (m, 2H), 2.29-2.25 (m,1H), 2.17-2.04 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 239.0. I-111

¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H),7.74 (s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 4.85 (dd, J = 10.4, 5.2 Hz, 1H),2.74-2.52 (m, 2H), 2.29-2.20 (m, 2H); LC/MS (ESI, m/z): [M + 1]⁺ =267.0. I-112

H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.80 (s, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.20 (d, J = 8.8 Hz, lH), 4.88 (d, J = 9.2, 4.8 Hz, 1H),2.83-2.75 (m, 2H), 2.45-2.43 (m, 1H), 2.35-2.32 (m, 1H); LC/MS (ESI,m/z): [M + 1]⁺ = 300.97, 302.97. I-83

¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, lH), 8.65 (t, J = 5.0 Hz, 2H),7.25 (dd, J = 6.4, 3.2 Hz, 1H), 4.71 (dd, J = 9.3, 7.0 Hz, 1H),2.78-2.66 (m, 1H), 2.63-2.54 (m, 1H), 2.36-2.21 (m, 2H); LC/MS (ESI,m/z): [M + 1]⁺ = 224.1. I-93

¹H NMR (400 MHz, DMSO-d₆) δ 12.78 (s, 1H), 11.07 (s, 1H), 8.02-8.01 (d,J = 6.8 Hz, 2H), 7.51-7.44 (m, 3H), 6.72 (s, 1H), 4.86-4.82 (m, 1H),2.81-2.72 (m, 1H), 2.67-2.33 (m, 3H); LC/MS (ESI, m/z): [M + 1]⁺ =316.1. I-89

¹H NMR (400 MHz, CDCl₃) δ 8.02 (br. s., 1H), 6.76 (s, 1H), 4.69 (dd, J =8.63, 6.00 Hz, 1H), 2.83-2.90 (m, 1H), 2.67-2.75 (m, 1H), 2.38-2.50 (m,8H); LC/MS (ESI, m/z): [M + 1]⁺ = 252.1. I-90

¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H), 6.54 (s, 1H), 5.06 (s, 1H),4.69 (dd, J = 10.4, 4.8 Hz, 1H), 2.68-2.52 (m, 2H), 2.45-2.20 (m, 2H);LC/MS (ESI, m/z): [M + 1]⁺ = 255.0. I-73

¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H), 7.33 (d, J = 1.2 Hz, 1H),6.99 (d, J = 1.2 Hz, 1H), 4.31-4.27 (dd, J = 4.8 Hz, J = 8.8 Hz, 1H),3.66 (s, 3H), 2.57-2.51 (m, 2H), 2.17- 2.01 (m, 2H); LC/MS (ESI, mz):[M + 1]⁺ = 226.1. I-105

¹H NMR (400 MHz, DMSO-d₆) δ 12.50 (s, 1H), 10.92 (s, 1H), 7.23 (s, 1H),6.99 (s, 1H), 4.38-4.25 (m, 1H), 2.58-2.52 (m, 2H), 2.15 (m, 1H),2.05-1.90 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ = 212.1. I-72

¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H), 7.74-7.72 (dd, J = 1.2 Hz, J= 6.4 Hz, 1H), 7.29-7.28 (dd, J = 1.2 Hz, J = 3.6 Hz, 1H), 7.11-7.08(dd, J = 3.6 Hz, J = 6.4 Hz, 1H), 4.08-4.04 (dd, J = 4.4 Hz, J = 9.2 Hz,1H), 2.55-2.47 (m, 2H), 2.17-2.12 (m, 1H), 1.92-1.87 (m, 1H); LC/MS(ESI, m/z): [M + 1]⁺ = 228.0. I-80

¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 7.58 (s, 1H), 6.47 (s, 1H),3.91-3.87 (dd, J = 4.8 Hz, 72 = 4.4 Hz, 1H), 2.58-2.51 (m, 2H), 2.29 (s,3H), 2.18-2.10 (m, 1H), 1.90-1.81 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ =226.1. I-97

¹H NMR (400 MHz, CDCl₃) δ 9.02 (d, J = 2.8 Hz, 1H), 8.23 (d, J = 8.4 Hz,1H), 8.08-7.99 (m, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H),7.60-7.47 (m, 2H), 4.61 (t, J = 4.5 Hz, 1H), 3.08-2.96 (m, 1H),2.72-2.66 (m, 1H), 2.50-2.34 (m, 2H); LC/MS (ESI, m, z): [M + 1]⁺ =273.1 I-96

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 7.49 (dd, J = 5.9, 3.2 Hz,2H), 7.21-7.14 (m, 2H), 4.88 (dd, J = 10.8, 5.2 Hz, 1H), 2.76-2.67 (m,1H), 2.63-2.55 (m, 1H), 2.44-2.37 (m, 1H), 2.33-2.23 (m, 1H); LC/MS(ESI, m/z): [M + 1]⁺ = 262.0. I-94

¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (br. s., 1H), 11.04 (br. s., 1H), 7.52(s, 1H), 7.46 (d, J = 8.50 Hz, 1H), 7.16 (dd, J = 8.50, 2.00 Hz, 1H),4.88 (dd, J = 10.82, 5.07 Hz, 1H), 2.69-2.77 (m, 1H), 2.55-2.62 (m, 1H),2.35-2.45 (m, 1H), 2.21- 2.35 (m, 1H); LC/MS (ESI, m/z): [M + 1]⁺ =296.0.

Example 28. Synthesis of 4-((2,6-dioxopiperidin-3-yl)thio)benzonitrile(I-67)

4-Mercaptobenzonitrile (28.2)

To a solution of 4-fluorobenzonitrile (5 g, 41.3 mmol) in DMF (50 mL),Na₂S (3.54 g, 45 mmol) was added. The reaction solution was stirred atr.t. overnight. 1M NaOH (500 mL) was added and the aqueous layer waswashed with CH₂Cl₂, acidified to pH ˜1-2 with 6N HCl and extracted withCH₂Cl₂, The combined organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. To the residue was added1000 HCl (200 mL) and cooled to 0° C. Then zine dust (20 g) was addedand the mixture was stirred for 1 h. The EA was added and the mixturewas stirred for an additional 30 min. The organic layer was separatedand washed with water and brine, dried over anhydrous Na₂SO₄, filtered,concentrated and purified by column chromatography to give4-mercaptobenzonitrile (1.0 g, 18.2%) as solid. LC/MS (ESI, m/z):[M+1]⁺=135.0.

4-((2,6-Dioxopiperidin-3-yl)thio)benzonitrile (I-67)

To a solution of 4-mercaptobenzonitrile (67.5 mg, 0.5 mmol) in DMF (5mL), 3-bromopiperidine-2,6-dione (115 mg, 0.6 mmol), Cs₂CO₃ (244 mg,0.75 mmol) were added. The reaction mixture was stirred at r.t for 3hours. The reaction mixture was diluted with H₂O (50 mL), extracted withEA (50 mL×2). The combined organic layer was washed with brine (50mL×3), dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo. Theresidue was purified by column (PE/EA=2/1) to give4-((2,6-dioxopiperidin-3-yl)thio)benzonitrile (31.7 mg, 26% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 7.79 (d, J=8.8Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 4.65 (dd, J=9.4, 4.8 Hz, 1H), 2.69-2.61(m, 1H), 2.59-2.56 m, 1H), 2.33-2.24 (m, 1H), 2.08-2.00 (m, 1H); LC/MS(ESI, m/z): [M+1]⁺=247.0.

Example 29. Synthesis of 3-((3-bromophenyl)thio)piperidine-2,6-dione(I-108) and 3-((3-ethylphenyl)thio)piperidine-2,6-dione (I-121)

3-((3-Bromophenyl)thio)piperidine-2,6-dione (I-108)

To a stirred solution of 3-bromopiperidine-2,6-dione (150 mg, 0.785 mol)in CH₃CN (15 mL) was added 3-bromobenzenethiol (193.1 mg, 1.021 mol),Cs₂CO₃ (332.8 mg, 1.021 mol) at r.t. The reaction mixture was stirred atr.t. for 2 h. The mixture was filtered and the filtrate was concentratedin vacuo. The residue was purified via column chromatography(DCM/EtOAc=5%-80%) to give 3-((3-bromophenyl)thio)piperidine-2,6-dione(158.1 mg, 67.1%) as a colorless oil. H NMR (400 Mz, CDCl₃) δ 7.76 (s,1H), 7.70 (t, J=1.7 Hz, 1H), 7.48 (dd, J=8.0, 1.7 Hz, 2H), 7.23 (t,J=8.0, 1H), 3.97 (t, J=5.0 Hz, 1H), 2.89-2.82 (m, 1H), 2.67-2.61 (m,1H), 2.39-2.33 (m, 1H), 2.20-2.15 (m, 1H); LC/MS (ESI, m/z):[M+1]⁺=300.0/301.9.

3-((3-ethylphenyl)thio)piperidine-2,6-dione (I-121)

To a solution of 3-((3-bromophenyl)thio)piperidine-2,6-dione (107 mg,0.358 mmol) in THE (25 mL) was added ethylboronic acid (39.7 mg, 0.537mmol), Ag₂O (273.7 mg, 1.18 mmol), K₂CO₃ (148.2 mg, 1.073 mmol) andPd(dppf)Cl₂ (39.3 mg, 0.054 mmol) at r.t. under nitrogen. The reactionwas heated at reflux under nitrogen for 12 h. The mixture was cooled tor.t., and filtered. The filtrate was concentrated in vacuo. The residuewas purified via reverse phase column chromatography (CH₃CN/H₂O=5%-80%)to give 3-((3-ethylphenyl)thio)piperidine-2,6-dione (19.8 mg, 22.2%) asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (s, 1H), 7.36 (d, J=12.3Hz, 2H), 7.26 (dd, J=8.4, 6.7 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 3.96 (t,J=4.6 Hz, 1H), 2.97-2.79 (m, 1H), 2.73-2.55 (m, 3H), 2.32 (m, 1H),2.24-2.09 (m, 1H), 1.24 (t, J=7.6 Hz, 3H); LC/MS (ESI, m/z):[M+1]⁺=250.1.

Example 30. Synthesis of3-((3-(hydroxymethyl)phenyl)thio)piperidine-2,6-dione (I-127)

(3-Mercaptophenyl)methanol (30.2)

To a stirred solution of 3-mercaptobenzoic acid (1 g, 6.5 mmol) in THE(10 mL) was added LiAlH₄ (246 mg, 13 mmol) at 0° C. portion wise. Afteraddition, the mixture was stirred at room temperature under N₂overnight. The reaction mixture was quenched by addition of NaSO₄·10H₂Oat 0° C., filtered, the filtrate was concentrated to give crude product,which was purified by CC on silica gel eluting with PE:EA=4:1 to give(3-mercaptophenyl)methanol as a colorless oil (200 mg, yield 22.0%). ¹HNMR (400 MHz, DMSO-d₆) δ 7.25 (s, 1H), 7.11-7.22 (m, 2H), 7.02-7.08 (m,1H), 5.35 (s, 1H), 5.19 (t, J=5.69 Hz, 1H), 4.43 (d, J=5.63 Hz, 2H).

3-((3-(Hydroxymethyl)phenyl)thio)piperidine-2,6-dione (I-127)

I-127 was synthesized via the same method as I-95. ¹H NMR (400 MHz,CDCl₃) δ 8.43 (br. s., 1H), 7.55 (s, 1H), 7.39-7.48 (m, 1H), 7.25-7.36(m, 2H), 4.66 (s, 2H), 3.96 (t, J=4.69 Hz, 1H), 2.95-2.79 (m, 1H),2.65-2.55 (m, 1H), 2.25-2.38 (m, 1H), 2.10-2.21 (m, 1H); LC/MS (ESI,m/z): [M+1]⁺=252.1.

Example 31. Synthesis of3-((2,6-dioxopiperidin-3-yl)thio)-2-methylbenzoic acid (I-137)

3-Mercapto-2-methylbenzoic acid (31.2)

To a stirred solution of 3-(chlorosulfonyl)-2-methylbenzoic acid (1.0 g,4.3 mmol) in AcOH (20 mL) was added dropwise a suspension of stannouschloride dihydrate (4.8 g, 21.4 mmol) in conc. HCl and water (20 mL,V/V=4:1) at r.t. After addition, the reaction mixture was heated to 80°C. and stirred at this temperature for 1 hour under nitrogen atmosphere.The reaction mixture was cooled to room temperature, poured intoice-water, filtered and dried to give 3-mercapto-2-methylbenzoic acidcrude (0.72 g, quan.) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.74 (d, J=2.1 Hz, 1H), 7.35 (dd, J=8.0, 2.1 Hz, 1H), 7.18 (d, J=8.0 Hz,1H), 5.58 (s, 1H), 2.44 (s, 3H).

3-((2,6-Dioxopiperidin-3-yl)thio)-2-methylbenzoic acid (I-137)

I-137 was synthesized via the same method as I-95. ¹H NMR (400 MHz,DMSO-d₆) δ 10.90 (s, 1H), 7.90 (m, 1H), 7.56 (dd, J=7.9, 1.2 Hz, 1H),7.30 (d, J=7.9 Hz, 1H), 4.29-4.25 (m, 1H), 2.56-2.49 (m, 5H), 2.24-2.16(m, 1H), 2.01-1.89 (m, 1H); LC/MS (ESI, m/z): [M+Na]⁺=302.0.

Example 32. Synthesis of 3-((4-ethylphenyl)sulfinyl)piperidine-2,6-dione(I-64) and 3-((4-ethylphenyl)sulfonyl)piperidine-2,6-dione (I-65)

To a stirred solution of 3-((4-ethylphenyl)thio)piperidine-2,6-dione(130 mg, 0.522 mmol) in DCM (10 mL) was added m-CPBA (224.5 mg, 0.783mol) at r.t. The reaction mixture was stirred at r.t. for 0.5 h. Themixture was extracted with EtOAc (50 mL×2). The combined organic layerwas washed with brine, dried and concentrated in vacuo. The mixture waspurified via column chromatography (Petroleum ether/EtOAc=5%-80%) togive 3-((4-ethylphenyl)sulfinyl)piperidine-2,6-dione (47.8 mg, 34.6%) asa white solid and 3-((4-ethylphenyl)sulfonyl)piperidine-2,6-dione (67.1mg, 45.7%) as a yellow solid. I-64: ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s,1H), 7.58 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 3.51 (dd, J=7.9,5.7 Hz, 1H), 3.04-2.92 (m, 1H), 2.74 (q, J=7.6 Hz, 2H), 2.60-2.41 (m,2H), 1.96-1.93 (m, 1H), 1.28 (t, J=7.6 Hz, 3H); LC/MS (ESI, m/z):[M+1]⁺=266.1. I-65: ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H), 7.81 (d,J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 4.04 (dd, J=5.7, 3.4 Hz, 1H),3.18-3.13 (m, 1H), 2.92-2.83 (m, 1H), 2.78-2.66 (m, 3H), 2.40-2.35 (m,1H), 1.29 (t, J=7.6 Hz, 3H); LC/MS (ESI, m/z): [M+1]⁺=282.1.

Example 33. Synthesis of2-((2,6-dioxopiperidin-3-yl)thio)-N,N-dimethylisonicotinamide (I-131)and 2-((2,6-dioxopiperidin-3-yl)thio)-N,N-dimethylisonicotinamide(I-132)

2-Chloroisonicotinoyl chloride (33.2)

To a mixture of 2-chloroisonicotinic acid (1.58 g, 10 mmol) and DMF (twodrops) in DCM (20 mL) was added (COCl)₂ (2.54 g, 20 mmol) dropwise, themixture was stirred at refluxing for 1 h. After the reaction, themixture was concentrated, the residue was utilized for next step withoutfurther purification.

2-Chloro-N-methylisonicotinamide (33.3)

To a mixture of TEA (1.52 mg, 15 mmol) and methanamine (372 mg, 12 mmol)in DCM (20 mL) was added 2-chloroisonicotinoyl chloride (1.76 g, 10mmol), the mixture was stirred at r.t. for 0.5 h. To the mixture wasadded H₂O (50 mL), extracted with DCM (20 mL×2). The combined organiclayer was washed with brine (50 mL×3), dried over Na₂SO₄, filtered,concentrated in vacuo and purified via pre-TLC (Petroleumether/EtOAc=2/1) to give 2-chloro-N-methylisonicotinamide (1.52 g, 89.4%yield) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=171.0.

2-Mercapto-N-methylisonicotinamide (33.4)

To a mixture of 2-chloro-N-methylisonicotinamide (340 mg, 2 mmol) in DMF(5 mL) was added NaSH (224 mg, 4 mmol), the mixture was stirred at 130°C. for overnight. To the residue was added H₂O (10 mL), extracted withEtOAc (10 mL×2). The combined organic layer was washed with brine (50mL×3), dried over Na₂SO₄, filtered, concentrated in vacuo and purifiedvia pre-TLC (DCM/MeOH=40/1) to give 2-mercapto-N-methylisonicotinamide(160 mg, 47.6% yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=169.0.

2-((2,6-Dioxopiperidin-3-yl)thio)-N-methylisonicotinamide (I-131)

To a mixture of 3-bromopiperidine-2,6-dione (236 mg, 1.24 mmol) and2-mercapto-N-methylisonicotinamide (160 mg, 0.95 mmol) in DMF (8 mL) wasadded Cs₂CO₃ (466 mg, 1.43 mmol), the mixture was stirred at r.t. for0.5 h. To the mixture was added H₂O (50 mL), extracted with EtOAc (20mL×2). The combined organic layer was washed with brine (50 mL×3), driedover Na₂SO₄, filtered, concentrated in vacuo and purified via pre-TLC(DCM/MeOH=1/1) to give2-((2,6-dioxopiperidin-3-yl)thio)-N-methylisonicotinamide (36.6 mg,13.7% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s,1H), 8.72-8.71 (m, 1H), 8.54 (d, J=4.2 Hz, 1H), 7.67 (s, 1H), 7.48-7.46(m, 1H), 4.86-4.82 (m, 1H), 2.79 (s, 3H), 2.85-2.67 (m, 1H), 2.59-2.52(m, 1H), 2.33-2.15 (m, 2H); LC/MS (ESI, m/z): [M+1]⁺=280.0.

2-((2,6-Dioxopiperidin-3-yl)thio)-N,N-dimethylisonicotinamide (I-132)

I-132 was synthesized via the same method as I-131 substitutingdimethylamine for reaction with 33.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.94(s, 1H), 8.48-8.47 (d, J=5.2 Hz, 1H), 7.37 (s, 1H), 7.14-7.12 (d, J=5.2Hz, 1H), 4.85-4.81 (m, 1H), 2.97 (s, 3H), 2.85 (s, 3H), 2.75-2.66 (m,1H), 2.59-2.50 (m, 1H), 2.32-2.14 (m, 2H); LC/MS (ESI, m/z):[M+1]⁺=294.0.

Example 34. Synthesis of 6-((2,6-dioxopiperidin-3-yl)thio)nicotinic acid(I-133)

A mixture of 6-chloronicotinic acid (1 g, 6.35 mmol), thiourea (580 mg,7.62 mmol) in CH₃CN (10 mL) was refluxed overnight. The precipate wasfiltered, the filter cake was collected and dried to get a yellow solid(1.6 g). The solid was resolved in 1M NaOH (12.7 mL) and stirred at roomtemperature for 2 h. Then 1M HCl was added to acidified the mixture toPh=5-6. The precipitate was collected and dried, which was used directlyin the next step without further purification (900 mg, yield: 89.7%). ¹HNMR (400 MHz, DMSO-d₆) δ 13.77 (br. s., 1H), 13.24 (br. s., 1H), 8.04(s, 1H), 7.55-7.81 (m, 1H), 7.31 (d, J=9.13 Hz, 1H); LC/MS (ESI, m/z):[M+1]⁺=156.1.

6-((2,6-Dioxopiperidin-3-yl)thio)nicotinic acid (I-133)

I-133 was synthesized via the same method as I-95. ¹H NMR (400 MHz,DMSO-d₆) δ 13.35 (br. s., 1H), 10.98 (s, 1H), 8.96-8.77 (m, 1H), 8.09(dd, J=8.38, 2.25 Hz, 1H), 7.49 (d, J=8.38 Hz, 1H), 4.91 (dd, J=10.51,5.13 Hz, 1H), 2.67-2.79 (m, 1H), 2.55-2.50 (m, 1H), 2.37-2.16 (m, 2H);LC/MS (ESI, m/z): [M+1]⁺=267.0.

Example 35. Synthesis of2-((2,6-dioxopiperidin-3-yl)thio)isonicotinamide (I-130)

4-Carbamoylpyridin-2-yl carbamimidothioate (35.2)

To a stirred solution of 2-chloroisonicotinamide (1 g, 6.386 mol) inCH₃CN (20 mL) was added thiourea (729.1 mg, 9.58 mol) at r.t. Thereaction mixture was heated at 82° C. overnight. The reaction mixturewas cooled to r.t. and filtered. The filtrate was concentrated in vacuo.The residue was purified via reverse phase column chromatography(MeOH/H₂O=5%-80%) to give 4-carbamoylpyridin-2-yl carbamimidothioate(890.1 mg, 71.1%) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=197.0

2,2′-Disulfanediyldiisonicotinamide (35.3)

To a stirred solution of 4-carbamoylpyridin-2-yl carbamimidothioate (890mg, 4.54 mmol) in H₂O (10 mL) was added NaOH (181.6 g, 4.54 mol) at r.t.The reaction mixture was heated to 40° C. for 1 h. The mixture wascooled to r.t. and the mixture was acidified to Ph=6.0 with 1 N HCl aq.to afford yellow solid. The solid was filtered and dried in vacuo togive 2,2′-disulfanediyldiisonicotinamide (490 mg, 70.1%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 2H), 7.73 (d, J=6.4 Hz, 4H),7.68 (d, J=1.6 Hz, 2H), 7.01 (dd, J=6.4, 1.6 Hz, 2H).

2-((2,6-Dioxopiperidin-3-yl)thio)isonicotinamide (I-130)

To a stirred solution of 2,2′-disulfanediyldiisonicotinamide (164 mg,0.536 mmol) in DMF (5 mL) was added sodium hyposulfite (186.5 mg, 1.072mmol) and K₂CO₃ (148 mg, 1.072 mmol) at r.t. The reaction mixture wasstirred at r.t. for 1 h. 3-bromopiperidine-2,6-dione (205 mg, 1.072mmol) was added to the above reaction mixture and the mixture wasstirred at r.t. for 2 hs. LCMS showed complete consumption of thestarting material. The mixture was filtered and concentrated in vacuo.The mixture was purified via reverse phase column chromatography(CH₃CN/H₂O=5%-80%) to give2-((2,6-dioxopiperidin-3-yl)thio)isonicotinamide (196.7 mg, 69.2%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.54 (dd, J=5.2,1.4 Hz, 1H), 8.22 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.50 (dd, J=5.2,1.4 Hz, 1H), 4.85 (dd, J=10.3, 5.1 Hz, 1H), 2.80-2.66 (m, 1H), 2.62-2.52(m, 1H), 2.36-2.15 (m, 2H); LC/MS (ESI, m/z): [M+1]⁺=266.0.

Example 36. Synthesis of 2-((2,6-dioxopiperidin-3-yl)thio)nicotinamide(I-140)

2-Mercaptonicotinamide (36.2)

A suspension of 2-mercaptonicotinic acid (4.0 mmol, 620 mg) in 20 mLtoluene and thionyl chloride (3.3 g, 28.0 mmol) was heated to reflux for3 h. The reaction mixture was cooled to room temperature and thenconcentrated in vacuum. The residue was added 10 mL toluene andconcentrated again in vacuum. The obtained acid chloride wassubsequently solved in a mixture of ammonium chloride (856 mg, 16.0mmol), concentrated ammonia (5 mL) and 3 mL of water and stirred at roomtemperature overnight. After treatment with NaBH₄ (148 mg, 4.0 mmol) for1 h, the mixture was concentrated in vacuo. The residue was purified viacolumn chromatography (DCM:MeOH=40:1 to DCM:MeOH=10:1) to give2-mercaptonicotinamide as a brown solid (246 mg, yield 40%). ¹H NMR (400MHz, DMSO-d₆) δ 13.98 (s, 1H), 10.06 (s, 1H), 8.49 (dd, J=7.6, 1.9 Hz,1H), 7.96-7.90 (m, 2H), 7.01 (dd, J=7.6, 6.0 Hz, 1H).

2-((2,6-Dioxopiperidin-3-yl)thio)nicotinamide (I-140)

To a mixture of 2-mercaptonicotinamide (200 mg, 1.3 mmol) in CH₃CN (10mL) was added 3-bromopiperidine-2,6-dione (374 mg, 1.95 mmol), K₂CO₃(443.7 mg, 1.361 mmol) at r.t. The reaction was stirred at r.t for 16 h.LC-MS showed complete consumption of the starting material. The mixturewas concentrated in vacuo. The residue was purified by CC on silica geleluting with CH₃CN:DCM=10:1 to CH₃CN:DCM=1:1 to give2-((2,6-dioxopiperidin-3-yl)thio)nicotinamide (130 mg, 30%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 8.47 (dd, J=4.8, 1.7Hz, 1H), 8.05 (s, 1H), 7.94 (dd, J=7.7, 1.7 Hz, 1H), 7.60 (s, 1H), 7.22(dd, J=7.7, 4.8 Hz, 1H), 4.77 (dd, J=9.9, 5.3 Hz, 1H), 2.76-2.62 (m,1H), 2.56-2.49 (m, 1H), 2.33-2.09 (m, 2H); LC/MS (ESI, m/z):[M+1]⁺=266.1.

Characterization data for further compounds prepared by the above methodare presented in Table 6 below. Compounds in Table 6 were prepared bymethods substantially similar to those described to prepare I-140, where36.2 was replaced with the reagent as indicated in Table 6.

TABLE 6 Cpnd # Reagent Compound Characterization I-141

¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H), 8.47 (dd, J = 4.9, 1.8 Hz,1H), 7.64 (dd, J = 7.5, 1.8 Hz, 1H), 7.24 (dd, J = 7.5, 4.9 Hz, 1H),4.89 (dd, J = 10.4, 5.2 Hz, 1H), 3.00 (s, 3H), 2.81 (s, 3H), 2.71-2.68(m, 1H), 2.56-2.49 (m, 1H), 2.26-2.07 (m, 2H); LC/MS (ESI, m/z): [M +1]⁺ = 294.0. I-142

¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s, 1H), 8.64 (s, 1H), 8.48 (dd, J =4.8, 1.8 Hz, 1H), 7.86 (dd, J = 7.7, 1.8 Hz, 1H), 7.23 (dd, J = 7.7, 4.8Hz, 1H), 4.79 (dd, J = 9.9, 5.2 Hz, 1H), 3.58-3.49 (m, 4H), 3.49-3.42(m, 2H), 3.39 (t, J = 5.8 Hz, 2H), 3.24 (s, 3H), 2.71-2.68 (m, 1H),2.56- 2.49 (m, 1H), 2.26-2.07 (m, 2H); LC/MS (ESI, m/z): [M + 1]⁺ =368.0.

Example 37. Synthesis of3-((4-(4-methyloxazol-2-yl)pyridin-2-yl)thio)piperidine-2,6-dione(I-138)

2-(2-Chloropyridin-4-yl)-4-methyloxazole (37.2)

To a stirred solution of 2-chloroisonicotinamide (1.2 g, 7.69 mmol) intoluene (40 mL) was added 1-bromopropan-2-one (1.58 g, 11.5 mmol) andsilver trifluoromethanesulfonate (3.0 g, 11.5 mmol). After addition, thereaction mixture was heated to 60° C. and stirred at this temperaturefor 17 hours under nitrogen atmosphere. The reaction mixture was cooledto room temperature, diluted with EA and filtered. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EA:PE=1:4) to give2-(2-chloropyridin-4-yl)-4-methyloxazole (0.35 g, 23.5%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=5.1 Hz, 1H), 7.92 (s, 1H),7.82-7.77 (m, 1H), 7.55-7.50 (m, 1H), 2.27 (s, 3H).

3-((4-(4-Methyloxazol-2-yl)pyridin-2-yl)thio)piperidine-2,6-dione(I-138)

I-138 was synthesized via the same method as I-133. ¹H NMR (400 MHz,DMSO-d₆) δ 10.97 (s, 1H), 8.56 (d, J=5.2 Hz, 1H), 8.06 (m, 1H), 7.80 (s,1H), 7.61 (dd, J=5.2, 1.4 Hz, 1H), 4.87 (dd, J=10.3, 5.2 Hz, 1H),2.77-2.68 (m, 1H), 2.60-2.54 (m, 1H), 2.37-2.20 (m, 2H), 2.19 (s, 3H);LC/MS (ESI, m/z): [M+1]⁺=304.0.

Example 38. Synthesis of3-((4-(2H-tetrazol-5-yl)pyridin-2-yl)thio)piperidine-2,6-dione (I-139)

2-Chloro-4-(2H-tetrazol-5-yl)pyridine (38.2)

To a stirred solution of 2-chloroisonicotinonitrile (1.0 g, 7.24 mmol)in toluene (25 mL) was added di(n-butyl)tin oxide (0.9 g, 3.62 mmol) andazidotrimethylsilane (4.2 g, 36.2 mmol). After addition, the reactionmixture was heated to 120° C. and stirred at this temperature for 17hours under nitrogen atmosphere. The reaction mixture was cooled to roomtemperature, quenched with MeOH and concentrated in vacuo. The residuewas diluted with EA, washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (EA:PE=1:4) to give2-chloro-4-(2H-tetrazol-5-yl)pyridine (1.0 g, 76.3%) as a yellow solid.LC/MS (ESI, m/z): [M+1]⁺=182.1.

3-((4-(2H-Tetrazol-5-yl)pyridin-2-yl)thio)piperidine-2,6-dione (I-139)

I-139 was synthesized via the same method as I-133. ¹H NMR (400 MHz,DMSO-d₆) δ 11.04 (s, 1H), 8.71 (dd, J=5.2, 1.5 Hz, 1H), 8.06-7.93 (m,1H), 7.80 (dd, J=5.2, 1.5 Hz, 1H), 5.03-4.84 (m, 1H), 2.92-2.73 (m, 1H),2.73-2.58 (m, 1H), 2.50-2.24 (m, 2H); LC/MS (ESI, m/z): [M+1]⁺=291.0.

Example 39. Synthesis of3-((1-cyclopropyl-1H-benzo[d]imidazol-2-yl)thio)piperidine-2,6-dione(I-70)

2-Chloro-1-cyclopropyl-1H-benzo[d]imidazole (39.2)

To a mixture of 2-chloro-1H-benzo[d]imidazole (1.53 g, 10 mmol) in DMF(15 mL) was added NaH (600 mg, 15 mmol) at 0° C., the mixture wasstirred at 0° C. for 0.5 h. Then bromocyclopropane (3.63 g, 30 mmol) wasadded to the above solution and stirred at r.t. for overnight. To themixture was added H₂O (50 mL), extracted with EtOAc (20 mL×2). Thecombined organic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered, concentrated in vacuo. The residue was purified via pre-TLC(Petroleum ether/EtOAc=8/1) to give the title compound (20 mg, 1% yield)as a colorless oil. LC/MS (ESI, m/z): [M+1]⁺=193.1.

1-Cyclopropyl-1H-benzo[d]imidazole-2-thiol (39.3)

To a mixture of 2-chloro-1-cyclopropyl-1H-benzo[d]imidazole (20 mg, 0.1mmol) in EtOH (5 mL) was added thiourea (12 mg, 0.15 mmol), the mixturewas stirred at 90° C. for 1 h. The reaction mixture was concentrated invacuo. The residue was diluted with H₂O (10 mL), extracted with EtOAc(10 mL×2). The combined organic layer was washed with brine (50 mL),dried over anhydrous Na₂SO₄, filtered and concentrated. The residue wasutilized for next step without further purification. LC/MS (ESI, m/z):[M+1]⁺=191.1.

3-((1-Cyclopropyl-1H-benzo[d]imidazol-2-yl)thio)piperidine-2,6-dione(I-70)

To a mixture of 3-bromopiperidine-2,6-dione (30 mg, 0.11 mmol) and1-cyclopropyl-1H-benzo[d]imidazole-2-thiol (20 mg, 0.105 mmol) in DMF (5mL) was added Cs₂CO₃ (41 mg, 0.126 mmol), the mixture was stirred atr.t. for 0.5 h. To the mixture was added H₂O (50 mL), extracted withEtOAc (20 mL×2). The combined organic layer was washed with brine (50mL), dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo andpurified via pre-TLC (Petroleum ether/EtOAc=1/1) to give3-((1-cyclopropyl-1H-benzo[d]imidazol-2-yl)thio)piperidine-2,6-dione (21mg, 65.6% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s,1H), 7.57-7.54 (m, 1H), 7.49-7.47 (m, 1H), 7.22-7.16 (m, 2H), 6.01-5.92(m, 1H), 5.20-5.17 (m, 1H), 5.00-4.90 (m, 2H), 4.86-4.85 (m, 2H),2.78-2.69 (m, 1H), 2.61-2.55 (m, 1H), 2.45-2.38 (m, 1H), 2.35-2.25 (m,1H); LC/MS (ESI, m/z): [M+1]⁺=302.1.

Example 40. Synthesis of3-((1-(tert-butyl)-1H-benzo[d]imidazol-2-yl)thio)piperidine-2,6-dione(I-63)

N-(tert-Butyl)-2-nitroaniline (40.2)

A mixture of 1-fluoro-2-nitrobenzene (5 g, 35.46 mmol), tert-butylamine(12.9 g, 177 mmol), K₂CO₃ (9.68 g, 70 mmol) in DMF (50 mL) was stirredat 60° C. for 2 days. The mixture was cooled to room temperature, pouredinto water (200 mL), extracted with EtOAc (3×200 mL). The combinedorganic layers were washed with water, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by CC on silica geleluting with PE:EA=100:3 to give n-(tert-butyl)-2-nitroaniline (6 g,yield 87.2%) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=195.0.

N¹-(tert-butyl)benzene-1,2-diamine (40.3)

To a solution of N-(tert-butyl)-2-nitroaniline (2 g, 10.3 mmol) in MeOH(5 mL) was added 10% palladium on activated carbon (500 mg, 0.471 mmol).The mixture was stirred at room temperature under H₂ for 4 h. Themixture was filtered. The filtrate was concentrated in vacuo, theresidue was purified by silica gel column chromatography (PE/EA=2:1) togive N1-(tert-butyl)benzene-1,2-diamine (500 mg, yield 29.4%) as ayellow oil. LC/MS (ESI, m/z): [M+1]⁺=165.0.

1-(tert-Butyl)-1,3-dihydro-2H-benzo[d]imidazole-2-thione (40.4)

A mixture of N¹-(tert-butyl)benzene-1,2-diamine (316 mg, 1.93 mmol),di(1H-imidazol-1-yl)methanethione (1.03 g, 5.78 mmol) in EtOH (5 mL) wasrefluxed overnight. The mixture was cooled to room temperature,concentrated in vacuo. The residue was purified by CC on silica geleluting with PE:EA=4:1 to give1-(tert-butyl)-1,3-dihydro-2H-benzo[d]imidazole-2-thione (65 mg, yield16.2%) as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=207.0.

3-((1-(tert-Butyl)-1H-benzo[d]imidazol-2-yl)thio)piperidine-2,6-dione(I-63)

I-63 was synthesized via the same method as I-95. ¹H NMR (400 MHz,DMSO-d₆) δ 10.99 (s, 1H), 7.71-7.82 (m, 1H), 7.42-7.52 (m, 1H),7.05-7.16 (m, 2H), 5.05 (dd, J=10.63, 5.25 Hz, 1H), 2.70-2.80 (m, 1H),2.54-2.64 (m, 1H), 2.29-2.45 (m, 2H), 1.86 (s, 9H); LC/MS (ESI, m/z):[M+1]⁺=318.1.

Example 41. Synthesis of1-(1-methyl-5-phenyl-1H-pyrazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(I-88)

2,3-Dibromo-3-phenylpropanenitrile (41.2)

To a stirred solution of cinnamonitrile (2.5 g, 19.38 mmol) in MeOH (50mL) was added Br₂ (6.2 g, 38.76 mmol) dropwise at 0° C. Then thereaction mixture was warmed to room temperature and stirred overnight.The resulting mixture was poured into water (50 mL) and basified withsolid NaHCO₃. The resulting mixture was extracted with EtOAc (3*50 mL).The combined organic layers were concentrated under reduced pressure.The residue was purified by CC on silica gel eluting with PE:EA=10:1 toPE:EA=4:1 to give 2,3-dibromo-3-phenylpropanenitrile (3.2 g) as a oil.(yield, 57.7%). LC/MS (ESI, m/z): [M+1]⁺=290.1.

1-Methyl-5-phenyl-1H-pyrazol-3-amine (41.3)

To a solution of 2,3-dibromo-3-phenylpropanenitrile (2 g, 7.0 mmol) inMeOH (10 mL) was added 40% methylhydrazine (805 mg, 7.0 mmol). Thereaction mixture was heated to 90° C. and stirred overnight. Then themixture was concentrated under reduced pressure, the residue waspurified by CC on silica gel eluting with DCM:MeOH=10:1 to give1-methyl-5-phenyl-1H-pyrazol-3-amine (500 mg, yield 41.2%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.30-7.56 (m, 5H), 5.55 (s, 1H), 4.60(br. s., 2H), 3.58 (s, 3H); LC/MS (ESI, m/z): [M+1]⁺=174.0.

1-(1-Methyl-5-phenyl-1H-pyrazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(I-88)

To a solution of 1-methyl-5-phenyl-1H-pyrazol-3-amine (527 mg, 3.05mmol) in toluene (10 mL) was added acrylic acid (263 mg, 3.65 mmol). Thereaction mixture was heated to 100° C. and stirred overnight. Then themixture was concentrated under reduced pressure, the residue wasdissolved in AcOH (5 mL), urea (366 mg, 6.10 mmol) was added and themixture was stirred at 120° C. for 2 days. The mixture was cooled toroom temperature, concentrated under reduced pressure, the residue waspurified by prep-HPLC to give1-(1-methyl-5-phenyl-1H-pyrazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(13.5 mg, yield 1.6%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.44 (s, 1H), 7.35-7.59 (m, 5H), 6.64 (s, 1H), 4.01 (t, J=6.75 Hz, 2H),3.78 (s, 3H), 2.69 (t, J=6.75 Hz, 2H); LC/MS (ESI, m/z): [M+1]⁺=271.1.

Characterization data for further compounds prepared by the above methodare presented in Table 7 below. Compounds in Table 7 were prepared bymethods substantially similar to those described to prepare I-140, where41.3 was replaced with the reagent as indicated in Table 7.

TABLE 7 Cpnd # Reagent Compound Characterization I-76

¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 7.60 (d, J = 2.25 Hz, 1H),6.45 (d, J = 2.25 Hz, 1H), 3.95 (t, J = 6.75 Hz, 2H), 3.76 (s, 3H), 2.65(t, J = 6.75 Hz, 2H); LC/MS (ESI, m/z): [M + 1]⁺ = 195.1. I-106

¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.3 l (d, J = 2.0 Hz, 1H), 6.21(d, J = 2.0 Hz, 1H), 4.61 (s, 2H), 3.91 (s, 3H), 3.42 (t, J = 6.8 Hz,2H), 2.34 (t, J = 6.8 Hz, 2H); LC/MS (ESI, m/z): [M + 1]⁺ = 209.1. I-143

¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H), 7.72 (dd, J = 6.8, 2.0 Hz,1H), 7.47 (dd, J = 6.8, 2.0 Hz, 1H), 6.26 (t, J = 6.8 Hz, 1H), 3.55 (t,J = 6.7 Hz, 2H), 3.48 (s, 3H), 2.65 (t, J = 6.7 Hz, 2H); LC/MS (ESI,m/z): [M + 1]⁺ = 222.1.

Example 42. Synthesis of5-(1-methyl-1H-indol-3-yl)thiazolidine-2,4-dione (I-71)

5-Bromothiazolidine-2,4-dione (42.2)

To a mixture of thiazolidine-2,4-dione (42.2 g, 360 mmol) in AcOH (60mL) at 85° C. was added a solution of Br₂ (57.7 g, 360 mmol) in AcOH (10mL) dropwise. The reaction mixture was heated to 85° C. and stirred for1 h, then the mixture was cooled to r.t. and poured into water (800 mL).The mixture was extracted with EtOAc (50 mL×2). The combined organiclayer was washed with brine (50 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified via columnchromatography (Petroleum ether/EtOAc=10/1) to give5-bromothiazolidine-2,4-dione (55 g, 78.5% yield) as a white solid.LC/MS (ESI, m/z): [M+1]⁺=195.9.

5-(1-Methyl-1H-indol-3-yl)thiazolidine-2,4-dione (I-71)

A stirred solution of AgOTf (771 mg, 3 mmol) was cooled to −78° C. underN2 and 1-methyl-1H-indole (262 mg, 2 mmol) was added in portions. Then asolution of 5-bromothiazolidine-2,4-dione (314 mg, 1.6 mmol) in DCM (10mL) was added dropwise and the mixture was stirred at −78° C. for 3 h.To the mixture was added H₂O (50 mL), extracted with DCM (20 mL×2). Thecombined organic layer was washed with brine (50 mL×3), dried overNa₂SO₄, filtered, concentrated in vacuo and purified via columnchromatography (Petroleum ether/EtOAc=5/1) to give5-(1-methyl-1H-indol-3-yl)thiazolidine-2,4-dione (55.3 mg, 14% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 7.48-7.40 (m,3H), 7.22-7.19 (t, J=7.6 Hz, 1H), 7.10-7.06 (t, J=7.4 Hz, 1H), 6.12 (s,1H), 3.77 (s, 3H); LC/MS (ESI, m/z): [M+1]⁺=247.0.

Example 43. Synthesis of 5-(3-oxopiperazin-1-yl)thiazolidine-2,4-dione(I-82)

5-(2-Oxo-4-phenylpiperazin-1-yl)thiazolidine-2,4-dione (I-82)

To a mixture of 4-phenylpiperazin-2-one (176 mg, 1.0 mmol) in THE (15mL) was added NaH (120 mg, 3.0 mmol) at 0° C., the mixture was stirredat 0° C. for 0.5 h. Then 5-bromothiazolidine-2,4-dione (784 mg, 4.0mmol) in THF (5 mL) was added dropwise, The mixture was stirred at 0° C.for 15 min. To the mixture was added H₂O (50 mL), extracted with EtOAc(20 mL×2). The combined organic layer was washed with brine (50 mL×3),dried over Na₂SO₄, filtered, concentrated in vacuo and purified viacolumn chromatography (Petroleum ether/EtOAc=4/1) to give5-(2-oxo-4-phenylpiperazin-1-yl)thiazolidine-2,4-dione (1.6 mg, 0.55%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.31 (s, 1H),7.26-7.18 (m, 2H), 6.96-6.94 (d, J=8.0 Hz, 2H), 6.84-6.80 (t, J=7.4 Hz,1H), 6.54 (s, 1H), 3.97-3.81 (m, 2H), 3.61-3.46 (m, 4H); LC/MS (ESI,m/z): [M+1]⁺=292.0.

5-(3-Oxopiperazin-1-yl)thiazolidine-2,4-dione (I-77)

I-77 was synthesized via the same method as I-82. ¹H NMR (400 MHz,DMSO-d₆) δ□12.24 (s, 1H), 7.94 (s, 1H), 6.12 (s, 1H), 3.30-3.11 (m, 3H),2.89-2.78 (m, 2H), 2.56-2.52 (m, 1H); LC/MS (ESI, m/z): [M+1]⁺=216.0.

Example 44. Synthesis of2-Imino-5-(1-methyl-1H-indazol-3-yl)thiazolidin-4-one (I-81)

2-Hydroxy-2-(1-methyl-1H-indazol-3-yl)acetonitrile (44.2)

A solution of NaCN (386 mg, 7.875 mmol) in H₂O (1 mL) was added to asolution of 1-methyl-1H-indazole-3-carbaldehyde (840 mg, 5.25 mmol) andAcOH (473 mg, 7.875 mmol) in DME (10 mL) and the mixture was stirred atr.t. overnight. To the mixture was added H₂O (50 mL), extracted withEtOAc (20 mL×2). The combined organic layers were washed with brine (50mL), dried over Na₂SO₄. The solid was filtered, the filtrate wasconcentrated in vacuum and purified via column chromatography (Petroleumether/EtOAc=4/1) to give2-hydroxy-2-(1-methyl-1H-indazol-3-yl)acetonitrile (850 mg, 86.6% yield)as a white solid.

2-Imino-5-(1-methyl-1H-indazol-3-yl)thiazolidin-4-one (I-81)

To a mixture of 2-hydroxy-2-(1-methyl-1H-indazol-3-yl)acetonitrile (570mg, 3.0 mmol) and thiourea (463 mg, 6.0 mmol) in DME (10 mL) was addedconc. HCl (1 mL), the reaction mixture was stirred at 100° C. overnight.To the mixture was added H₂O (50 mL), extracted with EtOAc (20 mL×2).The combined organic layers were washed with brine (50 mL), dried overNa₂SO₄. The solid was filtered, the filtrate was concentrated in vacuumand purified via column chromatography (Petroleum ether/EtOAc=8/1) togive 2-imino-5-(1-methyl-1H-indazol-3-yl)thiazolidin-4-one (284 mg,37.8% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s,1H), 10.50 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.45(t, J=7.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 5.81 (s, 1H), 4.04 (s, 3H);LC/MS (ESI, m/z): [M+1]⁺=247.1.

Example 45. Synthesis of5-(1-methyl-1H-indazol-3-yl)thiazolidine-2,4-dione (I-91)

To a solution of 2-imino-5-(1-methyl-1H-indazol-3-yl)thiazolidin-4-one(52 mg, 0.2 mmol) in dioxane (10 mL) was added 8N H₂SO₄ (6 mL) and themixture was stirred at refluxing for 3 h. To the mixture was added H₂O(50 mL), extracted with EtOAc (20 mL×2). The combined organic layerswere washed with brine (50 mL×3), dried over Na₂SO₄. The solid wasfiltered, the filtrate was concentrated in vacuum and purified viacolumn chromatography (Petroleum ether/EtOAc=8/1) to give5-(1-methyl-1H-indazol-3-yl)thiazolidine-2,4-dione (1 mg, 2% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 7.68 (d, J=9.2Hz, 2H), 7.46 (t, J=16.0 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 6.32 (s, 1H),4.04 (s, 3H); LC/MS (ESI, m/z): [M+1]⁺=248.0.

Example 46. Synthesis of5-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)thiazolidine-2,4-dione(I-118)

2-Chloroquinoline-3-carbaldehyde (46.2)

POCl₃ (40 g, 260 mmol) was added dropwise to an ice-cold solution of DMF(6.8 g, 93 mmol) and the deep-red solution was stirred at 0° C. for 0.5h. N-phenylacetamide (5 g, 37 mmol) was added in portions and themixture was stirred at 0° C. for 0.5 h, then heated to 75° C. overnight.The mixture was poured into ice-water (200 mL) and stirred at 0° C. for0.5 h. The solid was filtered and recrystallized from EtOAc to give2-chloroquinoline-3-carbaldehyde (3.74 g, 53.4% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 8.70 (s, 1H), 8.02 (d,J=8.5 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.82 (ddd, J=8.4, 7.0, 1.4 Hz,1H), 7.64-7.55 (m, 1H).

2-Hydroxyquinoline-3-carbaldehyde (46.3)

2-chloroquinoline-3-carbaldehyde (2.26 g, 11.8 mmol) was dissolved in 4NHCl (45 mL) and refluxed for 2 h. Cooled to r.t. and filtered, the solidwas dried under reduce pressure to give2-hydroxyquinoline-3-carbaldehyde (1.88 g, 91.7% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 10.25 (s, 1H), 8.51(s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.66 (ddd, J=8.5, 7.3, 1.4 Hz, 1H),7.36 (d, J=8.3 Hz, 1H), 7.30-7.21 (m, 1H).

1-Methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (46.4)

To a mixture of 2-hydroxyquinoline-3-carbaldehyde (1.53 g, 8.85 mmol) inDMF (25 mL) was added NaH (531 mg, 13.3 mmol) at 0° C., the mixture wasstirred at 0° C. for 0.5 h. Then Mel (2.5 g, 17.7 mmol) was added, themixture was stirred at r.t. overnight. To the mixture was added H₂O (50mL), extracted with EtOAc (20 mL×2). The combined organic layers werewashed with brine (50 mL), dried over Na₂SO₄. The solid was filtered,the filtrate was concentrated in vacuum and purified via columnchromatography (Petroleum ether/EtOAc=4/1) to give1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (1.47 g, 89% yield)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.52 (s,1H), 8.01 (dd, J=7.8, 1.4 Hz, 1H), 7.80 (ddd, J=8.7, 7.2, 1.5 Hz, 1H),7.62 (d, J=8.6 Hz, 1H), 7.40-7.22 (m, 1H), 3.68 (s, 3H).

2-Hydroxy-2-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)acetonitrile (46.5)

A solution of NaCN (681 mg, 13.9 mmol) in H₂O (2 mL) was added to asolution of 1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (1.3 g,6.95 mmol) and AcOH (834 mg, 13.9 mmol) in DME (15 mL) and the mixturewas stirred at 45° C. for 0.5 h. To the mixture was added H₂O (50 mL),extracted with EtOAc (20 mL×2). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄. The solid was filtered, thefiltrate was concentrated in vacuum and purified via columnchromatography (Petroleum ether/EtOAc=4/1) to give2-hydroxy-2-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)acetonitrile (920mg, 61.7% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (s,1H), 7.89 (dd, J=7.8, 1.3 Hz, 1H), 7.69 (ddd, J=8.6, 7.2, 1.5 Hz, 1H),7.60 (d, J=8.5 Hz, 1H), 7.37-7.30 (m, 1H), 7.23 (d, J=6.1 Hz, 1H), 5.61(dd, J=6.1, 1.1 Hz, 1H), 3.69 (s, 3H).

2-chloro-2-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)acetonitrile (46.6)

To a mixture of2-hydroxy-2-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)acetonitrile (428mg, 2 mmol) and DMF (one drop) in DCM (8 mL) was added SOCl₂ (476 mg, 4mmol) at 0° C. The reaction mixture was stirred at refluxing for 0.5 h.To the mixture was added H₂O (50 mL), extracted with DCM (20 mL×2). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄. The solid was filtered, the filtrate was concentrated in vacuumto give 2-chloro-2-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)acetonitrile(464 mg, 100% yield) as a yellow solid.

5-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)thiazolidine-2,4-dione(I-118)

To a mixture of2-chloro-2-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)acetonitrile (232mg, 1.0 mmol) and thiourea (152 mg, 2.0 mmol) in DME (6 mL) was addedconc. HCl (2 mL), the mixture was stirred at 100° C. overnight. To themixture was added H₂O (50 mL), extracted with EtOAc (30 mL×2). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄. The solid was filtered, the filtrate was concentrated in vacuumand purified via column chromatography (Petroleum ether/EtOAc=1/1) togive 5-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)thiazolidine-2,4-dione(159.3 mg, 58.1% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.13 (s, 1H), 8.13 (s, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.71-7.66 (m, 1H),7.58 (d, J=8.8 Hz, 1H), 7.34 (t, J=7.4 Hz, 1H), 5.77 (s, 1H), 3.66 (s,3H); LC/MS (ESI, m/z): [M+1]⁺=275.0.

Example 47. Synthesis of1-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(I-144)

3-Bromo-1-oxo-1,8a-dihydroquinolin-1-ium (47.2)

To a solution of 3-bromoquinoline (1.04 g, 5.0 mmol) in 30 mL DCM wasadded m-CPBA (860 mg, 5.0 mmol) at 0° C. and stirred at rt for 16 h.LC-MS showed 3-bromoquinoline was consumed. The reaction mixture wasdiluted with aqueous NaHCO₃, ectrated with DCM (30 mL×3), the combinedorganic phases were washed with brine then dried over anhydrous Na₂SO₄.The solid was filtered and the filtrate was concentrated and purified bycolumn chromatography on silica gel (PE:EA=5:1 to 1:1) to give3-bromo-1-oxo-1,8a-dihydroquinolin-1-ium (900 mg, yield 80%) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J=1.6 Hz, 1H), 8.47 (d,J=8.8 Hz, 1H), 8.31 (s, 1H), 8.06 (dd, J=8.1, 1.4 Hz, 1H), 7.91-7.83 (m,1H), 7.80-7.76 (m, 1H).

3-Bromoquinolin-2(1H)-one (47.3)

To a solution of 3-bromo-1-oxo-1,8a-dihydroquinolin-1-ium (445 mg, 2.0mmol) in 15 mL DCM was added benzoyl chloride (337 mg, 2.4 mmol) at 0°C., then K₂CO₃ (414 mg, 3.0 mmol) in H₂O (15 mL) was added drop wise.The reaction mixture was stirred at r.t for 16 h. A lot of solid wasformed, the solid was filtered and washed with water and DCM to give3-bromoquinolin-2(1H)-one (365 mg, yield 70%) as off-white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 12.24 (br s, 1H), 8.51 (s, 1H), 7.68 (dd, J=7.9,1.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.24-7.20 (m,1H).

3-Bromo-1-methylquinolin-2(1H)-one (47.4)

To a mixture of 3-bromoquinolin-2(1H)-one (224 mg, 1.0 mmol) in DMF (4mL) was added CH₃I (210 mg, 1.5 mmol), K₂CO₃ (273 mg, 2.0 mmol) at r.t.The reaction was stirred at 60° C. for 16 h. The mixture wasconcentrated in vacuum. The residue was purified by columnchromatography on silica gel (PE:EA=5:1 to 1:1) to3-bromo-1-methylquinolin-2(1H)-one (132 mg, yield 82%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.75 (dd, J=7.8, 1.2 Hz, 1H),7.70-7.66 (m, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.36-7.24 (m, 1H), 3.71 (s,3H).

tert-Butyl (1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)carbamate (47.5)

To a mixture of 3-bromo-1-methylquinolin-2(1H)-one (100 mg, 0.42 mmol)in 1.4-dioxane (5 mL) was added Xant-phos (48 mg, 0.084 mmol), Pd(OAc)₂(20 mg, 0.084 mmol) and Cs₂CO₃ (274 mg, 0.84 mmol). The reaction wasstirred at 100° C. under N₂ in sealed tube for 16 h. The mixture wasconcentrated in vacuum. The residue was purified by columnchromatography on silica gel (PE:EA=10:1 to PE:EA=1:1) to givetert-butyl (1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)carbamate (75 mg,yield 71%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H),8.01 (s, 1H), 7.88-7.65 (m, 1H), 7.56-7.50 (m, 2H), 7.29 (ddd, J=8.0,6.2, 2.1 Hz, 1H), 3.73 (s, 3H), 1.50 (s, 9H).

3-Amino-1-methylquinolin-2(1H)-one (47.6)

To a solution of tert-butyl(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)carbamate (1.2 g, 4.38 mmol) inDCM (15 mL) was added TFA (5 mL), The reaction was stirred at r.t for 16h. The reaction mixture was concentrated and the crude product waswashed with EA to give 3-amino-1-methylquinolin-2(1H)-one (480 mg, yield63%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.38 (m, 2H),7.28-7.24 (m, 2H), 7.16-7.12 (m, 1H), 6.76 (s, 1H), 5.50 (s, 2H), 3.69(s, 3H).

3-((1-Methyl-2-oxo-1,2-dihydroquinolin-3-yl)amino)propanoic acid (47.7)

To a solution of 3-amino-1-methylquinolin-2(1H)-one (174 mg, 1.0 mmol)in Toluene (10 mL) was added acrylic acid (144 mg, 2.0 mmol) at r.t. Thereaction was stirred at 100° C. under N₂ in a sealed tube for 16 h.LC-MS showed 50% of the starting material remained. The reaction mixturewas concentrated to give crude product3-((1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)amino)propanoic acid whichwas used next step without further purification. LC/MS (ESI, m/z):[M+1]⁺=247.1.

1-(1-Methyl-2-oxo-1,2-dihydroquinolin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(I-144)

To a mixture of3-((1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)amino)propanoic acid (300 mgcrude, 1.0 mmol) in AcOH (10 mL) was added urea (180 mg, 3.0 mmol). Thereaction mixture was stirred at 100° C. under N₂ in sealed tube for 16h. The mixture was concentrated in vacuum. The residue was purified byHPLC to give1-(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(2.2 mg) as a white solid (two steps yield, 1%). ¹H NMR (400 MHz,DMSO-d₆) δ 10.44 (s, 1H), 8.02 (s, 1H), 7.77 (dd, J=7.8, 1.5 Hz, 1H),7.67 (ddd, J=8.6, 7.1, 1.5 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.35-7.31(m, 1H), 3.68 (s, 3H), 3.65 (d, J=6.7 Hz, 2H), 2.70 (t, J=6.7 Hz, 2H);LC/MS (ESI, m/z): [M+1]⁺=272.1.

Example 48. Synthesis of1-(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione(I-145) and1-(2-methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione(I-146)

N-Methyl-2-phenylacetamide (48.2)

A mixture of methyl 2-phenylacetate (10.0 g, 66.7 mmol) and NH₂CH₃ (15mL) in EtOH (10 mL) was stirred at 80° C. for 16 h. The mixture wascooled to room temperature then poured into water (500 mL), extractedwith EtOAc (3×200 mL), the combined organic layers were concentratedunder reduced pressure, the residue was purified by columnchromatography (petroleum ether:ethyl acetate=2:1) to give the productN-methyl-2-phenylacetamide (5.0 g, yield 50%) as a yellow solid. LC/MS(ESI, m/z): [M+1]⁺=150.1.

2-Methyl-1,4-dihydroisoquinolin-3(2H)-one (48.3)

To a mixture of N-methyl-2-phenylacetamide (10 g, 67 mmol),Paraformaldehyde (2.41 g, 81 mmol) in Eaton's reagent (20 mL) wasstirred at 80° C. for 1 h. The mixture was poured into water (500 mL),basified with 1N NaOH aqueous to pH around 8, extracted with EtOAc(3×200 mL), the combined organic layers were concentrated under reducedpressure, the residue was purified by column chromatography (petroleumether:ethyl acetate=2:1) to give2-methyl-1,4-dihydroisoquinolin-3(2H)-one (7.5 g, yield 75%) as a yellowsolid. LC/MS (ESI, m/z): [M+1]⁺=162.1.

4-(Hydroxyimino)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (48.4)

To a solution of 2-methyl-1,4-dihydroisoquinolin-3(2H)-one (805 mg, 5.0mmol) in THF (10 mL) was added NaHMDS (3.0 mL, 6.0 mmol) dropwise at−78° C. for 20 min. Then tert-butyl nitrite (5.0 g, 20.0 mmol) was addedand stirred at −78° C. for 1 h. The mixture was poured into NH₄Cl (100mL), extracted with EtOAc (3×200 mL), the combined organic layers wereconcentrated under reduced pressure, the residue was purified by columnchromatography (petroleum ether:ethyl acetate=2:1) to give4-(hydroxyimino)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (800 mg,yield 84%) as a white solid. LC/MS (ESI, m/z): [M+1]⁺=191.1.

4-Amino-2-methyl-1,4-dihydroisoquinolin-3(2H)-one hydrochloride (48.5)

To a solution of4-(hydroxyimino)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (700 mg, 3.68mmol) in EtOH (20 mL) was added 10% Pd/C (200 mg) and 3N HCl (5 mL). Thereaction mixture was stirred at room temperature under H₂ with 50 PSIfor 1 h. Filtered and concentrated to give crude which was washed withCH₃CN to give 4-amino-2-methyl-1,4-dihydroisoquinolin-3(2H)-onehydrochloride (340 mg, yield 72%) as white solid. LC/MS (ESI, m/z):[M+1]⁺=177.1.

3-((2-Methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)amino)propanoicacid (48.6)

A mixture of 4-amino-2-methyl-1,4-dihydroisoquinolin-3(2H)-onehydrochloride (150 mg, 0.7 mmol) and acrylic acid (259 mg, 3.7 mmol) intoluene (2 mL) in a seal tube was stirred at 110° C. for 48 h. Filteredto give3-((2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)amino)propanoicacid (100 mg, yield 50%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.69 (br s, 1H), 9.74 (br s, 1H), 7.68-7.66 (m, 1H), 7.46-7.39 (m, 3H),5.26 (s, 1H), 4.72-4.59 (m, 2H), 3.18-3.11 (m, 1H), 3.08 (s, 3H),3.07-3.00 (m, 1H), 2.78 (t, J=7.1 Hz, 2H); LC/MS (ESI, m/z):[M+1]⁺=249.0.

1-(2-Methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione(I-145)

To a solution of3-((2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)amino)propanoicacid (49 mg, 0.2 mmol) in AcOH (3 mL) was added urea (60 mg, 10.0 mmol).The reaction mixture was stirred at 100° C. with sealed tube overnight.The reaction mixture concentrated in vacuo and washed with CH₃CN to give1-(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dioneas brown solid (12 mg, yield: 22%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.35(s, 1H), 7.35-7.26 (m, 4H), 5.88 (d, J=1.6 Hz, 1H), 4.70 (dd, J=15.9,3.2 Hz, 1H), 4.43 (d, J=15.9 Hz, 1H), 3.28-3.22 (m, 1H), 3.15-3.08 (m,1H), 3.02 (s, 3H), 2.73-2.66 (m, 1H), 2.64-2.54 (m, 1H); LC/MS (ESI,m/z): [M+1]⁺=274.1.

1-(2-Methyl-3-oxo-2,3-dihydroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione(I-146)

To a solution of1-(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione(200 mg, 0.73 mmol) in DCE (30 mL) was added DDQ (1.66 g, 7.3 mmol), themixture was stirred at rt for 48 h. Filtered to give crude product whichwas washed with water, CH₃CN, DMF to give the product as yellow solid(40 mg, yield, 25%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.93 (s,1H), 7.66 (d, J=8.6 Hz, 1H), 7.53-7.25 (m, 2H), 7.00 (ddd, J=8.6, 4.8,2.8 Hz, 1H), 3.85-3.72 (m, 4H), 3.37 (t, J=6.0 Hz, 1H), 2.92 (ddd,J=16.6, 10.5, 6.1 Hz, 1H), 2.64 (dt, J=16.5, 5.1 Hz, 1H); LC/MS (ESI,m/z): [M+1]⁺=272.1.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1-15. (canceled)
 16. A method of treating a CRBN-mediated disorder,disease, or condition in a patient comprising administering to saidpatient a compound of Formula I-b or I-k′:

or a pharmaceutically acceptable salt thereof, wherein: X³ is a bivalentmoiety selected from a —C(R¹)F—, —CF₂—, and —C(R¹)₂—; L is —S—; each R¹is independently hydrogen, halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R,—N(R)₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂, —Si(OH)R₂, —Si(OH)₂R,—SiR₃, or an optionally substituted C₁₋₄ aliphatic; or two R¹ groups onthe same carbon are optionally taken together with their interveningatoms to form a 3-6 membered spiro fused ring or a 4-7 memberedheterocyclic ring having 1-2 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, and sulfur; two R¹ groups on adjacentcarbon atoms are optionally taken together with their intervening atomsto form a 3-7 membered saturated, partially unsaturated, carbocyclicring or heterocyclic ring having 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur, or a 7-13 memberedsaturated, partially unsaturated, bridged heterocyclic ring, or a spiroheterocyclic ring having 1-3 heteroatoms, independently selected fromboron, nitrogen, oxygen, silicon, and sulfur; each R is independentlyhydrogen or an optionally substituted group selected from C₁₋₆aliphatic, phenyl, a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, and sulfur, a 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from boron, nitrogen,oxygen, silicon, and sulfur, a 7-13 membered saturated, partiallyunsaturated, bridged heterocyclic ring, or a spiro heterocyclic ringhaving 1-3 heteroatoms, independently selected from boron, nitrogen,oxygen, silicon, and sulfur, and a 8-10 membered bicyclic heteroarylring having 1-4 heteroatoms, independently selected from boron,nitrogen, oxygen, silicon, and sulfur; or two R groups on the samenitrogen are optionally taken together with their intervening atoms toform a 4-8 membered saturated, partially unsaturated, or heteroarylmonocyclic ring having 0-1 heteroatom, in addition to the nitrogen,independently selected from boron, nitrogen, oxygen, silicon, andsulfur, or a 7-13 membered saturated, partially unsaturated, bridgedheterocyclic ring, or a spiro heterocyclic ring having 0-2 heteroatoms,in addition to the nitrogen, independently selected from boron,nitrogen, oxygen, silicon, and sulfur; each R² is independentlyhydrogen, halogen, —CN, —NO₂, —OR, —SR, —NR₂, —Si(OH)₂R, —Si(OH)(R)₂,—Si(R)₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,—N(R)S(O)₂R, —N(R)S(O)₂NR₂, —P(O)(OR)₂, —P(O)(NR₂)OR, —P(O)(NR₂)₂,optionally substituted C₁₋₆ aliphatic, optionally substituted phenyl,optionally substituted 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, and sulfur, optionally substituted 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur, optionallysubstituted 7-13 membered saturated, partially unsaturated, bridgedheterocyclic ring, or a spiro heterocyclic ring having 1-3 heteroatoms,independently selected from boron, nitrogen, oxygen, silicon, andsulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms, independently selected from boron, nitrogen, oxygen,silicon, and sulfur; Ring B is selected from a 3 to 7-membered saturatedor partially unsaturated carbocyclic ring, phenyl, 8-10 memberedbicyclic carbocyclic aromatic ring, 4-7 membered saturated or partiallyunsaturated heterocyclic ring having 1-2 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, and sulfur, 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, and sulfur, 7-13 membered saturated,partially unsaturated, bridged heterocyclic ring, or a spiroheterocyclic ring having 1-3 heteroatoms, independently selected fromboron, nitrogen, oxygen, silicon, and sulfur, or a 8-10 memberedbicyclic heteroaryl ring having 1-4 heteroatoms, independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur; wherein Ring B isoptionally further substituted with 1-2 oxo groups; m is 0, 1, 2, 3, or4; and n is 0, 1, 2, 3, or 4; provided that the compound is other thanthe following, or a pharmaceutically acceptable salt thereof:


17. The method of claim 16, wherein the CRBN-mediated disorder, disease,or condition is selected from proliferative disorders, neurologicaldisorders and disorders associated with transplantation.
 18. (canceled)19. The method of claim 17, wherein the proliferative disorder is ahematological cancer.
 20. The method of claim 17, wherein theproliferative disorder is a leukemia.
 21. The method of claim 20,wherein the leukemia is selected from acute leukemia, acutelymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acutemyelogenous leukemia, acute myeloid leukemia (AML), adult acutebasophilic leukemia, adult acute eosinophilic leukemia, adult acutemegakaryoblastic leukemia, adult acute minimally differentiated myeloidleukemia, adult acute monoblastic leukemia, adult acute monocyticleukemia, adult acute myeloblastic leukemia with maturation, adult acutemyeloblastic leukemia without maturation, adult acute myeloid leukemiawith abnormalities, adult acute myelomonocytic leukemia, adulterythroleukemia, adult pure erythroid leukemia, secondary acute myeloidleukemia, untreated adult acute myeloid leukemia, adult acute myeloidleukemia in remission, adult acute promyelocytic leukemia with PML-RARA,alkylating agent-related acute myeloid leukemia, prolymphocyticleukemia, and chronic myelomonocytic leukemia.
 22. The method of claim17, wherein the proliferative disorder is a lymphoma.
 23. The method ofclaim 22, wherein the lymphoma is selected from adult grade IIIlymphomatoid granulomatosis, adult nasal type extranodal NK/T-celllymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-celllymphoma, cutaneous B-Cell non-Hodgkin lymphoma, extranodal marginalzone lymphoma of mucosa-associated lymphoid tissue, hepatosplenic T-celllymphoma, intraocular lymphoma, lymphomatous involvement ofnon-cutaneous extranodal site, mature T-cell and NK-cell non-Hodgkinlymphoma, nodal marginal zone lymphoma, post-transplantlymphoproliferative disorder, recurrent adult Burkitt lymphoma,recurrent adult diffuse large cell lymphoma, recurrent adult diffusemixed cell lymphoma, recurrent adult diffuse small cleaved celllymphoma, recurrent adult grade III lymphomatoid granulomatosis,recurrent adult immunoblastic lymphoma, recurrent adult lymphoblasticlymphoma, recurrent adult T-cell leukemia/lymphoma, recurrent cutaneousT-cell non-Hodgkin lymphoma, recurrent grade 1 follicular lymphoma,recurrent grade 2 follicular lymphoma, recurrent grade 3 follicularlymphoma, recurrent mantle cell lymphoma, recurrent marginal zonelymphoma, recurrent mycosis fungoides and Sezary syndrome, recurrentsmall lymphocytic lymphoma, refractory chronic lymphocytic leukemia,refractory hairy cell leukemia, Richter syndrome, small intestinallymphoma, splenic marginal zone lymphoma, T-cell large granularlymphocyte leukemia, testicular lymphoma, Waldenstrom macroglobulinemia,adult T-cell leukemia-lymphoma, peripheral T-cell lymphoma, B-celllymphoma, Hodgkin's disease, cutaneous T-cell lymphoma, diffuse largeB-cell lymphoma, MALT lymphoma, mantle cell lymphoma, non-Hodgkinslymphoma, central nervous system lymphoma, refractory primary-cutaneouslarge B-cell lymphoma (Leg-type), relapsed or refractory chroniclymphocytic leukemia, refractory anemia, refractory anemia with excessblasts, refractory anemia with ringed sideroblasts, refractory cytopeniawith multilineage dysplasia, and secondary myelodysplastic syndromes.24. (canceled)
 25. The method of claim 17, wherein the neurologicaldisorder is Alzheimer's disease.
 26. (canceled)
 27. The method of claim17, wherein the disorder associated with transplantation isgraft-versus-host disease.
 28. The method of claim 16, wherein R′ isselected from hydrogen, halogen, —CN, —OR, —N(R)₂, and C₁₋₄ alkyl. 29.The method of claim 16, wherein R² is selected from hydrogen, halogen,—CN, —NO₂, —OR, —SR, —N(R)₂, —C(O)R, —N(R)C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O) OR, —N(R)C(O)NR₂,—N(R)S(O)₂R, optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or anoptionally substituted 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, and sulfur.30. The method of claim 16, wherein R² is an optionally substituted C₁₋₆aliphatic.
 31. The method of claim 16, wherein R² is an optionallysubstituted phenyl.
 32. The method of claim 16, wherein Ring B is a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from boron, nitrogen, oxygen,silicon, and sulfur.
 33. The method of claim 16, wherein Ring B is a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, and sulfur.
 34. The method ofclaim 16, wherein Ring B is a 7-13 membered saturated, partiallyunsaturated, bridged heterocyclic ring, or a spiro heterocyclic ringhaving 1-3 heteroatoms, independently selected from boron, nitrogen,oxygen, silicon, and sulfur.
 35. The method of claim 16, wherein Ring Bis an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms,independently selected from boron, nitrogen, oxygen, silicon, andsulfur.
 36. The method of claim 16, wherein Ring B is an 8-10 memberedbicyclic carbocyclic aromatic ring.
 37. The compound of claim 16,wherein

is selected from

triazolyl,


38. The method of claim 16, wherein said compound is selected from thefollowing:

I-4

I-5

I-6

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-58

I-60

I-61

I-62

I-63

I-66

I-67

I-68

I-69

I-70

I-72

I-73

I-74

I-75

I-79

I-80

I-83

I-84

I-85

I-86

I-87

I-89

I-90

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-104

I-105

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-116

I-117

I-120

I-121

I-122

I-123

I-126

I-127

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

or a pharmaceutically acceptable salt thereof.
 39. The method of claim16, wherein the compound is administered in a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, adjuvant, or vehicle.